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Targeted and Other Nontraditional Antineoplastic Therapy

Targeted therapy exerts antineoplastic activity against cancer cells by interfering with unique properties found in tumors or malignancies. The types of drugs can be small molecules, which are able to enter cells, or monoclonal antibodies Monoclonal antibodies Antibodies produced by a single clone of cells. Ebolavirus and Marburgvirus, which have targets outside of or on the surface of cells. Among the areas in malignant cells that are blocked or inhibited by targeted therapy are signal pathways (as seen in protein kinase Protein kinase A family of enzymes that catalyze the conversion of ATP and a protein to adp and a phosphoprotein. Interferons inhibitors), which lead to decreased proliferation and subsequent tumor Tumor Inflammation cell apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage. Other means of reducing cancer cells is by eliminating the capacity for DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure repair (seen in poly(ADP-ribose) polymerase inhibitors), blocking the ligand-receptor binding (growth factor inhibitors), and increasing immune activity against the neoplasm (immunotherapies). These agents are used in multiple types of cancer and in combination with traditional chemotherapeutic agents.

Last updated: Jun 1, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Cancer therapy development

  • Traditional chemotherapy Chemotherapy Osteosarcoma affects both cancer cells and normal cells.
  • A growing number of new anticancer agents (targeted therapy) are now used in addition to the traditional antineoplastic drugs.
    • Development is based on findings that molecular changes in cells drive progression to malignancy Malignancy Hemothorax.
    • Drugs are able to block the oncogenic pathway(s) with fewer cytotoxic Cytotoxic Parvovirus B19 effects on normal cells.

Targeted cancer therapy

  • Interfere with specific molecules that target particular pathways, affecting the growth and proliferation of cancer cells
  • There are different ways of disrupting pathways; these include prevention of receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors binding and intracellular binding and inhibition of kinases Kinases Macrolides and Ketolides.
  • Most of the available therapies are:
    • Small molecules: 
      • Compounds (that can enter cells) with intracellular targets (e.g., kinases Kinases Macrolides and Ketolides)
      • Inhibition of kinases Kinases Macrolides and Ketolides prevent further activation of different pathways (as seen in protein kinase Protein kinase A family of enzymes that catalyze the conversion of ATP and a protein to adp and a phosphoprotein. Interferons inhibitors)
      • Most drug names of protein kinase Protein kinase A family of enzymes that catalyze the conversion of ATP and a protein to adp and a phosphoprotein. Interferons inhibitors end with the syllable “-ib.”
    • Monoclonal antibodies Monoclonal antibodies Antibodies produced by a single clone of cells. Ebolavirus and Marburgvirus
      • Used for targets outside of or on the surface of the cells (e.g., growth factor receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors or receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors ligands)
      • Monoclonal antibody drug names end with the syllable “-mab.”
Schematic mechanism for receptor tyrosine kinase inhibition

Schematic mechanism for receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase inhibition. On the left, the image shows the structure of the receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors of the cell. On the cell surface lies the ligand-binding domain and the kinase domain (in this image, tyrosin kinase) is found intracellularly. On the right, the image shows how a monoclonal antibody can produce antineoplastic activity, which is via antibody-mediated inhibition of the ligand-binding domain. Small molecules which can enter cells, are able to produce inhibition of the ATP-binding ( tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase) domain.

Image by Lecturio.

Protein Kinase Inhibitors

Protein kinases Kinases Macrolides and Ketolides

  • There are > 500 different protein kinases Kinases Macrolides and Ketolides in the human genome Genome The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics:
  • Particular signal transduction Transduction The transfer of bacterial DNA by phages from an infected bacterium to another bacterium. This also refers to the transfer of genes into eukaryotic cells by viruses. This naturally occurring process is routinely employed as a gene transfer technique. Bacteriology cascades follow (e.g., BCR-ABL with tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids as a protein substrate Substrate A substance upon which the enzyme acts. Basics of Enzymes, RAF with serine Serine A non-essential amino acid occurring in natural form as the l-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines; pyrimidines; and other amino acids. Synthesis of Nonessential Amino Acids/threonine); modulating activities include:
    • Cell proliferation
    • Gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics expression
    • Metabolism
    • Membrane transport
    • Apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage
  • However, when kinases Kinases Macrolides and Ketolides are constitutively expressed → oncogenesis Oncogenesis The origin, production or development of cancer through genotypic and phenotypic changes which upset the normal balance between cell proliferation and cell death. Carcinogenesis generally requires a constellation of steps, which may occur quickly or over a period of many years. Carcinogenesis, such as that seen in the RAS-RAF-MEK-ERK pathway:
    • Signaling pathway involved in cell proliferation and differentiation
    • Activated in many cancers
    • Regulating signaling affects cancer growth.
  • Protein kinase Protein kinase A family of enzymes that catalyze the conversion of ATP and a protein to adp and a phosphoprotein. Interferons inhibitors:
    • Block the action of protein kinase Protein kinase A family of enzymes that catalyze the conversion of ATP and a protein to adp and a phosphoprotein. Interferons enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, which are often overexpressed in cancer.
    • Inhibiting protein kinases Kinases Macrolides and Ketolides is a mechanism also used in drugs to treat inflammatory conditions.

BCR-ABL kinase inhibitors

  • Philadelphia chromosome Philadelphia chromosome An aberrant form of human chromosome 22 characterized by translocation of the distal end of chromosome 9 from 9q34, to the long arm of chromosome 22 at 22q11. It is present in the bone marrow cells of 80 to 90 percent of patients with chronic myelocytic leukemia. Acute Lymphoblastic Leukemia translocation t(9;22) → BCR-ABL1 fusion gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
    • Fusion leads to constitutive activation of BCR-ABL → uncontrolled cell division Cell Division A type of cell nucleus division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. Cell Cycle → ↑ granulocytic production
    • Seen in CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia
  • Related agents:
    • Imatinib
    • 2nd-generation:
      • Dasatinib 
      • Nilotinib 
Table: BCR-ABL kinase inhibitors
Imatinib Dasatinib Nilotinib
Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is “what the body does to the drug,” whereas pharmacodynamics is “what the drug does to the body.” Pharmacokinetics and Pharmacodynamics
  • Inhibit BCR-ABL tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase (causing apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage of BCR-ABL positive cell lines)
  • Inhibit c-KIT, PDGFR
  • Imatinib: also inhibits stem-cell factor
Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics
  • Oral
  • Hepatic metabolism
  • Excretion: mostly in feces
Indications
  • CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia
  • Imatinib, dasatinib: ALL ( Ph pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance+)
  • Imatinib:
    • Systemic mastocytosis
    • CML CML Chronic myeloid leukemia is a malignant proliferation of the granulocytic cell line characterized by a fairly normal differentiation. The underlying genetic abnormality is the Philadelphia chromosome, an abbreviated chromosome 22, resulting from reciprocal (9;22)(q34;q11) translocation. Chronic Myeloid Leukemia
    • GIST GIST All tumors in the gastrointestinal tract arising from mesenchymal cells (mesoderm) except those of smooth muscle cells (leiomyoma) or schwann cells (schwannoma). Gastric Cancer
    • Dermatofibrosarcoma protuberans
    • CEL CEL Chronic eosinophilic leukemia (CEL) is a chronic myeloproliferative neoplasm caused by autonomous clonal proliferation of normal-appearing eosinophils, resulting in increased eosinophils in the peripheral blood and bone marrow. The disorder is a myeloid variant of hypereosinophilic syndrome (HES) and is associated with tissue infiltration leading to end-organ damage. Chronic Eosinophilic Leukemia
    • MDS MDS Myelodysplastic syndromes (MDS) are a group of clonal neoplasms with maturation defects characterized by dysplasia, cytopenia, and immature bone marrow precursors. Myelodysplastic syndromes can be idiopathic, or secondary to various injurious exposures such as cytotoxic chemotherapy, ionizing radiation, or environmental toxins. Myelodysplastic Syndromes/MPD
Adverse effects
  • Myelosuppression Myelosuppression Oxazolidinones
  • TLS
  • Hemorrhage
  • Cardiovascular events ( heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR))
  • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Dermatologic reactions (e.g., SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome, EM)
  • GI irritation
  • Nephrotoxicity Nephrotoxicity Glycopeptides
  • Hepatotoxicity Hepatotoxicity Acetaminophen
  • Myelosuppression Myelosuppression Oxazolidinones
  • TLS
  • Hemorrhage
  • Cardiovascular events
  • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Dermatologic reactions
  • Prolonged QT Prolonged QT Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers)
  • Pulmonary hypertension Pulmonary Hypertension Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies. Pulmonary Hypertension
Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation
CEL CEL Chronic eosinophilic leukemia (CEL) is a chronic myeloproliferative neoplasm caused by autonomous clonal proliferation of normal-appearing eosinophils, resulting in increased eosinophils in the peripheral blood and bone marrow. The disorder is a myeloid variant of hypereosinophilic syndrome (HES) and is associated with tissue infiltration leading to end-organ damage. Chronic Eosinophilic Leukemia: chronic eosinophilic leukemia Chronic eosinophilic leukemia Chronic eosinophilic leukemia (CEL) is a chronic myeloproliferative neoplasm caused by autonomous clonal proliferation of normal-appearing eosinophils, resulting in increased eosinophils in the peripheral blood and bone marrow. The disorder is a myeloid variant of hypereosinophilic syndrome (HES) and is associated with tissue infiltration leading to end-organ damage. Chronic Eosinophilic Leukemia
EM: erythema multiforme Erythema multiforme Erythema multiforme (EM) is an acute hypersensitivity reaction characterized by targetoid skin lesions with multiple rings and dusky centers. Lesions may be accompanied by systemic symptoms (e.g., fever) and mucosal lesions (e.g., bullae). Erythema Multiforme
GIST GIST All tumors in the gastrointestinal tract arising from mesenchymal cells (mesoderm) except those of smooth muscle cells (leiomyoma) or schwann cells (schwannoma). Gastric Cancer: GI stromal tumors
MDS MDS Myelodysplastic syndromes (MDS) are a group of clonal neoplasms with maturation defects characterized by dysplasia, cytopenia, and immature bone marrow precursors. Myelodysplastic syndromes can be idiopathic, or secondary to various injurious exposures such as cytotoxic chemotherapy, ionizing radiation, or environmental toxins. Myelodysplastic Syndromes/MPD: myelodysplastic/myeloproliferative diseases
PDGF: platelet-derived growth factor Platelet-derived growth factor Mitogenic peptide growth hormone carried in the alpha-granules of platelets. It is released when platelets adhere to traumatized tissues. Connective tissue cells near the traumatized region respond by initiating the process of replication. Hypertrophic and Keloid Scars
Ph pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance+: Philadelphia chromosome Philadelphia chromosome An aberrant form of human chromosome 22 characterized by translocation of the distal end of chromosome 9 from 9q34, to the long arm of chromosome 22 at 22q11. It is present in the bone marrow cells of 80 to 90 percent of patients with chronic myelocytic leukemia. Acute Lymphoblastic Leukemia–positive
SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome: Stevens-Johnson syndrome Stevens-Johnson syndrome Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome
TLS: tumor lysis syndrome Tumor lysis syndrome Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. Tumor Lysis Syndrome

BRAF kinase inhibitors

  • BRAF: 
    • Protein in the RAF family of serine Serine A non-essential amino acid occurring in natural form as the l-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines; pyrimidines; and other amino acids. Synthesis of Nonessential Amino Acids/threonine kinases Kinases Macrolides and Ketolides
    • Has an important role in mediating signals from RAS RAS Renal artery stenosis (RAS) is the narrowing of one or both renal arteries, usually caused by atherosclerotic disease or by fibromuscular dysplasia. If the stenosis is severe enough, the stenosis causes decreased renal blood flow, which activates the renin-angiotensin-aldosterone system (RAAS) and leads to renovascular hypertension (RVH). Renal Artery Stenosis to MEK, leading to proliferation 
    • Mutations → persistent intracellular signaling → malignancy Malignancy Hemothorax 
  • Related agents (block the activity of mutated BRAF):
    • Vemurafenib
    • Dabrafenib
Table: BRAF kinase inhibitors
Vemurafenib Dabrafenib*
Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is “what the body does to the drug,” whereas pharmacodynamics is “what the drug does to the body.” Pharmacokinetics and Pharmacodynamics Inhibit kinase activity of mutated BRAF (including V600 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations)
Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics
  • Oral
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: 57 hours (vemurafenib), 8 hours (parent drug: dabrafenib)
  • Excretion: feces
Indications
  • Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
  • Erdheim-Chester disease
  • Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
  • NSCLC
  • Thyroid cancer Thyroid cancer Thyroid cancer is a malignancy arising from the thyroid gland cells: thyroid follicular cells (papillary, follicular, and anaplastic carcinomas) and calcitonin-producing C cells (medullary carcinomas). Rare cancers are derived from the lymphocytes (lymphoma) and/or stromal and vascular elements (sarcoma). Thyroid Cancer
Adverse effects
  • Cardiovascular: prolonged QT Prolonged QT Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers), hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • Cutaneous malignancy Malignancy Hemothorax
  • Uveitis Uveitis Uveitis is the inflammation of the uvea, the pigmented middle layer of the eye, which comprises the iris, ciliary body, and choroid. The condition is categorized based on the site of disease; anterior uveitis is the most common. Diseases of the Uvea
  • Dermatologic reactions
  • Hepatotoxicity Hepatotoxicity Acetaminophen
  • Nephrotoxicity Nephrotoxicity Glycopeptides
  • Pancreatitis Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis
  • Fibroproliferative disorders
  • Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma sensitization
  • Cardiovascular: cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types, prolonged QT Prolonged QT Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers)
  • Cutaneous malignancy Malignancy Hemothorax
  • Uveitis Uveitis Uveitis is the inflammation of the uvea, the pigmented middle layer of the eye, which comprises the iris, ciliary body, and choroid. The condition is categorized based on the site of disease; anterior uveitis is the most common. Diseases of the Uvea
  • Dermatologic reactions
  • Febrile reactions
  • Hemorrhage
  • Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance
  • VTE VTE Obstruction of a vein or veins (embolism) by a blood clot (thrombus) in the bloodstream. Hypercoagulable States
Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation Hypersensitivity to the drug
*Combination with trametinib produces greater inhibitory activity.
NSCLC: non–small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer
VTE VTE Obstruction of a vein or veins (embolism) by a blood clot (thrombus) in the bloodstream. Hypercoagulable States: venous thromboembolism Venous thromboembolism Obstruction of a vein or veins (embolism) by a blood clot (thrombus) in the bloodstream. Hypercoagulable States

MEK inhibitors

Table: MEK inhibitors
Trametinib Cobimetinib
Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is “what the body does to the drug,” whereas pharmacodynamics is “what the drug does to the body.” Pharmacokinetics and Pharmacodynamics Inhibits MEK activation and kinase activity
Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics
  • Oral
  • Primarily deacetylation
  • Not a substrate Substrate A substance upon which the enzyme acts. Basics of Enzymes of CYP enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: 4–5 days
  • Excretion: feces
  • Oral
  • Hepatic metabolism
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: 44 hours
  • Excretion: feces
Indications
  • Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
  • NSCLC
  • Anaplastic thyroid cancer Thyroid cancer Thyroid cancer is a malignancy arising from the thyroid gland cells: thyroid follicular cells (papillary, follicular, and anaplastic carcinomas) and calcitonin-producing C cells (medullary carcinomas). Rare cancers are derived from the lymphocytes (lymphoma) and/or stromal and vascular elements (sarcoma). Thyroid Cancer
Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
Adverse effects
  • Myelosuppression Myelosuppression Oxazolidinones
  • Hepatotoxicity Hepatotoxicity Acetaminophen
  • Cardiovascular events ( heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR), ↓ LVEF)
  • Dermatologic reactions
  • Hemorrhage
  • Cutaneous cancers
  • Febrile reactions
  • Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance
  • Colitis Colitis Inflammation of the colon section of the large intestine, usually with symptoms such as diarrhea (often with blood and mucus), abdominal pain, and fever. Pseudomembranous Colitis, GI perforation Perforation A pathological hole in an organ, blood vessel or other soft part of the body, occurring in the absence of external force. Esophagitis
  • Ocular: retinal detachment Retinal detachment Retinal detachment is the separation of the neurosensory retina from the retinal pigmented epithelium and choroid. Rhegmatogenous retinal detachment, the most common type, stems from a break in the retina, allowing fluid to accumulate in the subretinal space. Retinal Detachment
  • VTE VTE Obstruction of a vein or veins (embolism) by a blood clot (thrombus) in the bloodstream. Hypercoagulable States
  • Myelosuppression Myelosuppression Oxazolidinones
  • Hepatotoxicity Hepatotoxicity Acetaminophen
  • Cardiovascular events ( heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR), ↓ LVEF)
  • Dermatologic reactions
  • Hemorrhage
  • Cutaneous cancers
  • Ocular: retinal detachment Retinal detachment Retinal detachment is the separation of the neurosensory retina from the retinal pigmented epithelium and choroid. Rhegmatogenous retinal detachment, the most common type, stems from a break in the retina, allowing fluid to accumulate in the subretinal space. Retinal Detachment, retinopathy Retinopathy Degenerative changes to the retina due to hypertension. Alport Syndrome
Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation Hypersensitivity to the drug
LVEF: left ventricular ejection fraction Ejection fraction Cardiac Cycle
NSCLC: non–small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer
VTE VTE Obstruction of a vein or veins (embolism) by a blood clot (thrombus) in the bloodstream. Hypercoagulable States: venous thromboembolism Venous thromboembolism Obstruction of a vein or veins (embolism) by a blood clot (thrombus) in the bloodstream. Hypercoagulable States

JAK inhibitors

  • Janus-associated kinases Kinases Macrolides and Ketolides (JAKs) are mediators of signals among cells, cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response, and growth factors in hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis and immune response.
    • Receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors interacts with a cytokine or growth factor → activate JAKs → tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids phosphorylation Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Post-translational Protein Processing → activate signal transducer Transducer A device placed on the patient’s body to visualize a target Ultrasound (Sonography) and activators of transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription (STATs)
    • STATs translocate to the nucleus Nucleus Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (cell nucleolus). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the endoplasmic reticulum. A cell may contain more than one nucleus. The Cell: Organelles transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription of effector genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure → effects include proliferation, differentiation, migration, apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage, and cell survival
  • Related agents:
    • Ruxolitinib (1st in class)
    • Agents with noncancer indications:
      • Baricitinib
      • Tofacitinib (approved for inflammatory conditions such as ulcerative colitis Colitis Inflammation of the colon section of the large intestine, usually with symptoms such as diarrhea (often with blood and mucus), abdominal pain, and fever. Pseudomembranous Colitis and rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis)
Table: JAK inhibitors
Ruxolitinib Barcitinib
Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is “what the body does to the drug,” whereas pharmacodynamics is “what the drug does to the body.” Pharmacokinetics and Pharmacodynamics Inhibit JAKs
Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics
  • Oral
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: 3–6 hours (ruxolitinib), 12 hours (baricitinib)
  • Hepatic metabolism
  • Excretion: mostly urine
Indications
  • Rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis
  • Off-label: COVID-19 COVID-19 Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that mainly affects the respiratory system but can also cause damage to other body systems (cardiovascular, gastrointestinal, renal, and central nervous systems). hospitalization Hospitalization The confinement of a patient in a hospital. Delirium (requiring oxygen)
Adverse effects
  • Myelosuppression Myelosuppression Oxazolidinones
  • Serious infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • ↑ Hepatic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
  • Cutaneous cancers
  • ↑ Lipid
  • Myelosuppression Myelosuppression Oxazolidinones
  • Serious infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease (including TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis)
  • ↑ Hepatic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
  • Cutaneous cancers
  • ↑ Lipid
  • Thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus
  • GI perforation Perforation A pathological hole in an organ, blood vessel or other soft part of the body, occurring in the absence of external force. Esophagitis
Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation Hypersensitivity to the drug
JAK: Janus-associated kinases Kinases Macrolides and Ketolides
COVID-19 COVID-19 Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that mainly affects the respiratory system but can also cause damage to other body systems (cardiovascular, gastrointestinal, renal, and central nervous systems). : coronavirus Coronavirus Coronaviruses are a group of related viruses that contain positive-sense, single-stranded RNA. Coronavirus derives its name from “κορώνη korṓnē” in Greek, which translates as “crown,” after the small club-shaped proteins visible as a ring around the viral envelope in electron micrographs. Coronavirus disease 2019

Cyclin-dependent kinase (CDK) inhibitors

  • CDKs are serine Serine A non-essential amino acid occurring in natural form as the l-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines; pyrimidines; and other amino acids. Synthesis of Nonessential Amino Acids/threonine protein kinases Kinases Macrolides and Ketolides that mediate signaling in the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle progression ( G0 G0 Cell Cycle/G1 to S phase S Phase Phase of the cell cycle following g1 and preceding g2 when the entire DNA content of the nucleus is replicated. It is achieved by bidirectional replication at multiple sites along each chromosome. Cell Cycle) and thus affect Affect The feeling-tone accompaniment of an idea or mental representation. It is the most direct psychic derivative of instinct and the psychic representative of the various bodily changes by means of which instincts manifest themselves. Psychiatric Assessment cell proliferation.
  • The complex of cyclin D and CDK → phosphorylate the retinoblastoma Retinoblastoma Retinoblastoma is a rare tumor but the most common primary intraocular malignancy of childhood. It is believed that the condition arises from a neuronal progenitor cell. Retinoblastoma can be heritable or non-heritable. Retinoblastoma gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics protein (RB1) → processes lead to induction of S-phase genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure.
  • Inappropriate cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle progression → tumorigenesis
  • Class of drugs identified by the syllable “-ciclib”
  • Related agents:
    • Palbociclib
    • Abemaciclib
    • Ribociclib
Table: CDK inhibitors
Palbociclib Abemaciclib
Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is “what the body does to the drug,” whereas pharmacodynamics is “what the drug does to the body.” Pharmacokinetics and Pharmacodynamics CDK inhibitor; prevents progression through the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle, leading to arrest at the G1 phase G1 Phase The period of the cell cycle preceding DNA replication in s phase. Subphases of g1 include ‘competence’ (to respond to growth factors), g1a (entry into g1), g1b (progression), and g1c (assembly). Progression through the g1 subphases is effected by limiting growth factors, nutrients, or inhibitors. Cell Cycle
Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics
  • Oral
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: approximately 30 hours (palbociclib), approximately 18 hours (abemaciclib)
  • Hepatic metabolism
  • Excretion: feces
Indications Advanced breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
Adverse effects
  • Myelosuppression Myelosuppression Oxazolidinones
  • Pulmonary toxicity Toxicity Dosage Calculation
  • ↑ Hepatic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
  • Myelosuppression Myelosuppression Oxazolidinones
  • Pulmonary toxicity Toxicity Dosage Calculation
  • ↑ Hepatic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
  • Thromboembolism Thromboembolism Obstruction of a blood vessel (embolism) by a blood clot (thrombus) in the blood stream. Systemic Lupus Erythematosus
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation Hypersensitivity to the drug

Bruton tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase (BTK) inhibitors

  • The BTKs are important for the survival, proliferation, chemotaxis Chemotaxis The movement of leukocytes in response to a chemical concentration gradient or to products formed in an immunologic reaction. Leukocyte Adhesion Deficiency Type 1, and adhesion Adhesion The process whereby platelets adhere to something other than platelets, e.g., collagen; basement membrane; microfibrils; or other ‘foreign’ surfaces. Coagulation Studies of B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions.
  • Inhibiting BTK is a mechanism used in treating B-cell malignancies.
  • Related agents:
    • Ibrutinib (1st generation)
    • Acalabrutinib (2nd generation, with higher selectivity for BTK)
Table: BTK inhibitors
Ibrutinib Acalabrutinib
Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is “what the body does to the drug,” whereas pharmacodynamics is “what the drug does to the body.” Pharmacokinetics and Pharmacodynamics Inhibit BTK, leading to reduced B-cell proliferation and tumor Tumor Inflammation growth
Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics
  • Oral
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: 4–6 hours (ibrutinib), 1 hour (acalabrutinib)
  • Hepatic metabolism
  • Excretion: feces
Indications
  • Graft-versus-host disease Graft-versus-host disease The clinical entity characterized by anorexia, diarrhea, loss of hair, leukopenia, thrombocytopenia, growth retardation, and eventual death brought about by the graft vs host reaction. Transfusion Reactions (chronic)
  • CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia/ SLL SLL Chronic Lymphocytic Leukemia
  • Mantle cell lymphoma Mantle cell lymphoma A form of non-Hodgkin lymphoma having a usually diffuse pattern with both small and medium lymphocytes and small cleaved cells. It accounts for about 5% of adult non-Hodgkin lymphomas in the United States and Europe. The majority of mantle-cell lymphomas are associated with a t(11; 14) translocation resulting in overexpression of the cyclin D1 gene. Non-Hodgkin Lymphomas
  • Marginal cell lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum
  • Waldenström macroglobulinemia Waldenström macroglobulinemia Non-Hodgkin Lymphomas
  • CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia/ SLL SLL Chronic Lymphocytic Leukemia
  • Mantle cell lymphoma Mantle cell lymphoma A form of non-Hodgkin lymphoma having a usually diffuse pattern with both small and medium lymphocytes and small cleaved cells. It accounts for about 5% of adult non-Hodgkin lymphomas in the United States and Europe. The majority of mantle-cell lymphomas are associated with a t(11; 14) translocation resulting in overexpression of the cyclin D1 gene. Non-Hodgkin Lymphomas
Adverse effects
  • Myelosuppression Myelosuppression Oxazolidinones
  • Cardiovascular effects (arrhythmias, hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension)
  • Hemorrhage
  • Serious infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • Secondary malignancies
  • Renal toxicity Toxicity Dosage Calculation
  • TLS
  • Myelosuppression Myelosuppression Oxazolidinones
  • Cardiovascular effects (arrhythmias)
  • Hemorrhage
  • Serious infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • Secondary malignancies
  • ↑ Hepatic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation Hypersensitivity to the drug
SLL SLL Chronic Lymphocytic Leukemia: small lymphocytic lymphoma Small Lymphocytic Lymphoma Chronic Lymphocytic Leukemia
TLS: tumor lysis syndrome Tumor lysis syndrome Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. Tumor Lysis Syndrome

Anaplastic lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum kinase (ALK) inhibitors

  • Anaplastic lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum kinase is a tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase that is noted to be aberrantly expressed in certain tumors, such as non–small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer (NSCLC).
  • The gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics ALK is able to form fusion genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure that become oncogenic drivers.
    • ALK-NPM fusion gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics anaplastic large cell lymphoma Anaplastic large cell lymphoma A systemic, large-cell, non-Hodgkin, malignant lymphoma characterized by cells with pleomorphic appearance and expressing the cd30 antigen. These so-called ‘hallmark’ cells have lobulated and indented nuclei. This lymphoma is often mistaken for metastatic carcinoma and malignant histiocytosis. Autosomal Dominant Hyperimmunoglobulin E Syndrome (ALCL)
    • EML4-ALK fusion gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics → found in some NSCLCs 
  • Related agents:
    • Crizotinib
    • Alectinib
    • Ceritinib
Table: ALK inhibitors
Crizotinib Alectinib Ceritinib
Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is “what the body does to the drug,” whereas pharmacodynamics is “what the drug does to the body.” Pharmacokinetics and Pharmacodynamics Inhibit ALK, preventing proliferation and survival of ALK-positive tumors
Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics
  • Oral
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: 42 hours
  • Hepatic metabolism
  • Excretion: feces
  • Oral
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: approximately 33 hours
  • Hepatic metabolism
  • Excretion: feces
  • Oral
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: 41 hours
  • Hepatic metabolism
  • Excretion: feces
Indications
  • NSCLC (ALK-positive), metastatic
  • Anaplastic large cell lymphoma Anaplastic large cell lymphoma A systemic, large-cell, non-Hodgkin, malignant lymphoma characterized by cells with pleomorphic appearance and expressing the cd30 antigen. These so-called ‘hallmark’ cells have lobulated and indented nuclei. This lymphoma is often mistaken for metastatic carcinoma and malignant histiocytosis. Autosomal Dominant Hyperimmunoglobulin E Syndrome (ALK-positive)
Adverse effects
  • Cardiovascular toxicity Toxicity Dosage Calculation ( bradycardia Bradycardia Bradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea. Bradyarrhythmias, prolonged QT Prolonged QT Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers))
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics and vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
  • Hepatotoxicity Hepatotoxicity Acetaminophen
  • Pulmonary toxicity Toxicity Dosage Calculation
Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation Hypersensitivity to the drug

Growth Factor Receptor Inhibitors

Epidermal growth factor receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (EGFR) agents

  • EGFR: 
    • Part of the ErbB family of growth factor receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors, with an important role in growth and differentiation of epithelial cells
    • Overexpressed in some cancers
    • Ligand binds to the EGFR extracellular domain → intracellular signaling (intracellular domain with tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase) by cross-phosphorylation leading to:
  • Monoclonal antibody inhibitors of EGFR:
    • Recognize the extracellular domain of EGFR, leading to:
    • Include:
      • Cetuximab 
      • Panitumumab
  • Protein tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase inhibitors (TKIs) of EGFR:
    • Enter the tumor Tumor Inflammation cells, inhibiting EGFR tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase
    • Include:
      • Gefitinib
      • 2nd-generation inhibitor: erlotinib, afatinib 
      • 3rd-generation inhibitor: osimertinib (for NSCLC previously treated with earlier generation of drugs and with T790M mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations)
Table: Monoclonal antibodies Monoclonal antibodies Antibodies produced by a single clone of cells. Ebolavirus and Marburgvirus binding EGFR
Cetuximab Panitumumab
Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is “what the body does to the drug,” whereas pharmacodynamics is “what the drug does to the body.” Pharmacokinetics and Pharmacodynamics
Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics
Indications
  • Metastatic colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer (KRAS wild type or without mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations)
  • Cetuximab: head and neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess, squamous cell cancer
Adverse effects
  • Rash Rash Rocky Mountain Spotted Fever (acneiform)
  • Pruritus Pruritus An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. Atopic Dermatitis (Eczema)
  • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • ↓ Mg
  • Interstitial lung disease
  • Cardiopulmonary arrest Cardiopulmonary arrest Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. Cardiac Arrest
Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation Hypersensitivity to drug or its components
Table: Protein tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase inhibitors of EGFR
Afatinib Erlotinib Gefitinib
Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is “what the body does to the drug,” whereas pharmacodynamics is “what the drug does to the body.” Pharmacokinetics and Pharmacodynamics Inhibitor of EGFR tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase
Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics
  • Oral (↓ absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption with fatty meals)
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: 37 hours
  • Minimal enzymatic metabolism
  • Excretion: feces
  • Oral (↑ absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption with food)
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: 36 hours
  • Hepatic metabolism
  • Excretion: feces
  • Oral
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: 48 hours
  • Hepatic metabolism
  • Excretion: feces
Indications NSCLC (with mutations)
  • NSCLC (with mutations)
  • Pancreatic cancer (advanced)
NSCLC (with EGFR mutations)
Adverse effects
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions rash Rash Rocky Mountain Spotted Fever
  • Anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Left ventricular dysfunction
  • Interstitial lung disease
  • Hepatotoxicity Hepatotoxicity Acetaminophen
  • Nephrotoxicity Nephrotoxicity Glycopeptides
  • Erlotinib: ↑ warfarin Warfarin An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. Anticoagulants anticoagulant activity
Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation Hypersensitivity to the drug or its components
EGFR: epidermal growth factor receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
NSCLC: non–small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer

Vascular endothelial growth factor Vascular endothelial growth factor A family of angiogenic proteins that are closely-related to vascular endothelial growth factor a. They play an important role in the growth and differentiation of vascular as well as lymphatic endothelial cells. Wound Healing receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (VEGFR) agents

  • Angiogenic growth factor
  • Important for tumors, which need intact vascular structures for growth.
  • Different ways and agents to inhibit VEGFR signaling:
    • Direct inhibitors of VEGFR tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase or VEGF TKIs:
      • Sorafenib (multikinase inhibitor)
      • Pazopanib (multikinase inhibitor)
      • Sunitinib
    • Monoclonal antibodies Monoclonal antibodies Antibodies produced by a single clone of cells. Ebolavirus and Marburgvirus targeting the VEGF ligand: 
      • Bevacizumab
      • Ramucirumab
    • Vascular endothelial growth factor Vascular endothelial growth factor A family of angiogenic proteins that are closely-related to vascular endothelial growth factor a. They play an important role in the growth and differentiation of vascular as well as lymphatic endothelial cells. Wound Healing (VEGF) trap or a soluble receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors made of extracellular domains of VEGFR (binding the VEGF ligand, thus ↓ signaling): Ziv-aflibercept 
Table: Agents inhibiting VEGFR by different mechanisms
Bevacizumab Ziv-aflibercept Sorafenib
Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is “what the body does to the drug,” whereas pharmacodynamics is “what the drug does to the body.” Pharmacokinetics and Pharmacodynamics Monoclonal antibody targeting VEGF ligand Recombinant fusion protein Fusion protein Proteins that catalyze membrane fusion. Measles Virus acting as a decoy receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors Inhibit VEGFR tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinases Kinases Macrolides and Ketolides (and also PDGF)
Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics
  • IV (for cancer)
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: 20 days in adults
  • Oral
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: 1–2 days
  • Hepatic metabolism
Indications
  • Advanced cervical cancer Cervical cancer Cervical cancer, or invasive cervical carcinoma (ICC), is the 3rd most common cancer in women in the world, with > 50% of the cases being fatal. In the United States, ICC is the 13th most common cancer and the cause of < 3% of all cancer deaths due to the slow progression of precursor lesions and, more importantly, effective cancer screening. Cervical Cancer
  • Metastatic CRC
  • Metastatic HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases
  • Recurrent GBM
  • NSCLC
  • Ovarian, fallopian tube Fallopian Tube A pair of highly specialized canals extending from the uterus to its corresponding ovary. They provide the means for ovum transport from the ovaries and they are the site of the ovum’s final maturation and fertilization. The fallopian tube consists of an interstitium, an isthmus, an ampulla, an infundibulum, and fimbriae. Its wall consists of three layers: serous, muscular, and an internal mucosal layer lined with both ciliated and secretory cells. Uterus, Cervix, and Fallopian Tubes: Anatomy, peritoneal cancer
  • RCC RCC Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma
Metastatic CRC
  • Advanced HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases
  • Advanced RCC RCC Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma
Adverse effects
  • Myelosuppression Myelosuppression Oxazolidinones
  • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
  • Heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR)
  • Hemorrhage
  • GI perforations
  • ↑ Arterial thromboembolic events (e.g., TIA TIA Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. Transient Ischemic Attack (TIA), stroke)
  • Wound healing Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. Wound Healing complications
  • Proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children
  • Bevacizumab: ↑ cardiotoxicity of anthracyclines Anthracyclines Organic compounds that have a tetrahydronaphthacenedione ring structure attached by a glycosidic linkage to the amino sugar daunosamine. Antitumor Antibiotics
Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation None listed
  • Hypersensitivity to the drug
  • Avoid use with carboplatin Carboplatin An organoplatinum compound that possesses antineoplastic activity. Alkylating Agents and Platinum and paclitaxel Paclitaxel A cyclodecane isolated from the bark of the pacific yew tree, taxus brevifolia. It stabilizes microtubules in their polymerized form leading to cell death. Microtubule and Topoisomerase Inhibitors (for lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer) as sorafenib ↑ their toxic effects
CRC: colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer
GBM: glioblastoma
HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases: hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases
NSCLC: non small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer
PDGF: platelet-derived growth factor Platelet-derived growth factor Mitogenic peptide growth hormone carried in the alpha-granules of platelets. It is released when platelets adhere to traumatized tissues. Connective tissue cells near the traumatized region respond by initiating the process of replication. Hypertrophic and Keloid Scars
RCC RCC Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma: renal cell carcinoma Renal cell carcinoma Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma
TIA TIA Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. Transient Ischemic Attack (TIA): transient ischemic attack Transient ischemic attack Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. Transient Ischemic Attack (TIA)
VEGFR: vascular endothelial growth factor Vascular endothelial growth factor A family of angiogenic proteins that are closely-related to vascular endothelial growth factor a. They play an important role in the growth and differentiation of vascular as well as lymphatic endothelial cells. Wound Healing receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors

Human epidermal growth factor receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors 2 (HER2) agents

  • HER2: also called Neu or ErbB2
  • Overexpression → intracellular tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase activation → oncogenic signaling
  • Overexpressed HER2: seen in up to 30% of breast cancers 
  • Monoclonal antibodies Monoclonal antibodies Antibodies produced by a single clone of cells. Ebolavirus and Marburgvirus against HER2/Neu:
    • Trastuzumab
    • Pertuzumab
  • TKI: lapatinib
Table: Agents inhibiting HER2
Trastuzumab Pertuzumab Lapatinib
Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is “what the body does to the drug,” whereas pharmacodynamics is “what the drug does to the body.” Pharmacokinetics and Pharmacodynamics Monoclonal antibody binding HER2 (extracellular domain) Dual kinase inhibitor (inhibits EGFR and HER2)
Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics
  • IV
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: approximately 5.8 days
  • Oral
  • Hepatic metabolism
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: approximately 24 hours
  • Excretion: feces
Indications
  • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Gastric cancer Gastric cancer Gastric cancer is the 3rd-most common cause of cancer-related deaths worldwide. The majority of cases are from adenocarcinoma. The modifiable risk factors include Helicobacter pylori infection, smoking, and nitrate-rich diets. Gastric Cancer
Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
Adverse effects
  • Cardiotoxicity: cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types
  • Pulmonary toxicity Toxicity Dosage Calculation
  • Renal toxicity Toxicity Dosage Calculation
  • Dermatologic reactions
  • Birth defects
  • Cardiotoxicity
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Birth defects
  • Cardiotoxicity
  • Hepatotoxicity Hepatotoxicity Acetaminophen
  • Pulmonary toxicity Toxicity Dosage Calculation
  • Myelosuppression Myelosuppression Oxazolidinones (with capecitabine Capecitabine A deoxycytidine derivative and fluorouracil prodrug that is used as an antineoplastic antimetabolite in the treatment of colon cancer; breast cancer and gastric cancer. Antimetabolite Chemotherapy)
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Dermatologic reactions
Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation Hypersensitivity to the drug

Platelet-derived growth factor Platelet-derived growth factor Mitogenic peptide growth hormone carried in the alpha-granules of platelets. It is released when platelets adhere to traumatized tissues. Connective tissue cells near the traumatized region respond by initiating the process of replication. Hypertrophic and Keloid Scars receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (PDGFR) agents

  • Platelet-derived growth factors (PDGFs) bind BIND Hyperbilirubinemia of the Newborn receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors and activate the receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors protein kinases Kinases Macrolides and Ketolides.
    • Important in the survival and proliferation of mesenchymal cells
    • Cancer growth facilitated by dysfunctional signaling and role in angiogenesis Angiogenesis Bartonella
  • TKIs (agents with PDGFR activity):
    • BCR-ABL kinase inhibitors: imatinib, dasatinib, nilotinib
    • VEGFR kinase inhibitors: sunitinib, sorafenib
  •  Monoclonal antibody targeting PDGFR: olaratumab
    • Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is “what the body does to the drug,” whereas pharmacodynamics is “what the drug does to the body.” Pharmacokinetics and Pharmacodynamics: binds PDGFRɑ, blocking activation of receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors and signaling
    • Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics: IV, with half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics of approximately 11 days
    • Indication: soft tissue Soft Tissue Soft Tissue Abscess sarcoma
    • Adverse effects:
      • Neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
      • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
      • Infusion-related reactions Infusion-related reactions Cancer Immunotherapy
      • Embryo Embryo The entity of a developing mammal, generally from the cleavage of a zygote to the end of embryonic differentiation of basic structures. For the human embryo, this represents the first two months of intrauterine development preceding the stages of the fetus. Fertilization and First Week/fetal harm
    • Contraindication: hypersensitivity to the drug

PARP Inhibitors

Poly(ADP-ribose) polymerase (PARP)

  • A product Product A molecule created by the enzymatic reaction. Basics of Enzymes of DNA damage DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a mutation or a block of DNA replication. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (pyrimidine dimers) or interstrand crosslinking. Damage can often be repaired (DNA repair). If the damage is extensive, it can induce apoptosis. DNA Repair Mechanisms repair genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure
  • Catalyzes the transfer of ADP-ribose to target proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis (process called PARylation)
  • Roles:
    • Important in base excision repair Base excision repair DNA Repair Mechanisms and nucleotide excision repair Nucleotide excision repair DNA Repair Mechanisms
    • Also involved in transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription and cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle regulation
  • Inhibiting PARP → ↓ repair capability → tumor Tumor Inflammation cell apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage and ↑ sensitivity of cells to other chemotherapeutic agents (e.g., alkylating drugs)

Inhibitors of PARP

  • Olaparib
  • Rucaparib
  • Niraparib
Table: PARP inhibitors
Olaparib Rucaparib Niraparib
Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is “what the body does to the drug,” whereas pharmacodynamics is “what the drug does to the body.” Pharmacokinetics and Pharmacodynamics PARP enzyme inhibitor
Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics
  • Oral
  • Metabolized by CYP3A
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: approximately 15 hours
  • Excretion: urine and feces
  • Oral
  • Hepatic metabolism (CYP2D6, CYP3A, CYP1A2)
  • Half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics: 26 hours
  • Excretion: urine and feces
Indications
  • Advanced ovarian cancer Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). Ovarian Cancer
  • Metastatic breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Metastatic pancreatic cancer
  • Metastatic prostate cancer Prostate cancer Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. Prostate Cancer
  • Advanced ovarian cancer Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). Ovarian Cancer
  • Metastatic, castration-resistant prostate cancer Prostate cancer Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. Prostate Cancer
Ovarian, fallopian tube Fallopian Tube A pair of highly specialized canals extending from the uterus to its corresponding ovary. They provide the means for ovum transport from the ovaries and they are the site of the ovum’s final maturation and fertilization. The fallopian tube consists of an interstitium, an isthmus, an ampulla, an infundibulum, and fimbriae. Its wall consists of three layers: serous, muscular, and an internal mucosal layer lined with both ciliated and secretory cells. Uterus, Cervix, and Fallopian Tubes: Anatomy or primary peritoneal cancer
Common adverse effects
Adverse effects
  • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism
  • Cardiovascular effects ( hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension)
  • Posterior reversible encephalopathy syndrome Posterior Reversible Encephalopathy Syndrome High-Risk Headaches
Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation Hypersensitivity to the drug None listed Hypersensitivity to the drug

Other Targeted Therapy, Immunotherapy, and Miscellaneous Agents

BCL2 inhibitors

  • The BCL2 protein family is involved in governing programmed cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death ( apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage).
    • Antiapoptotic proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis have BH1 and BH2 domains.
    • Proapoptotic proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis have BH3 domain.
  • When antiapoptotic proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis are promoted, there is increased cell survival, as seen in cancers such as CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia, in which BCL2 is overexpressed.
  • Related agent: venetoclax Venetoclax Chronic Lymphocytic Leukemia
    • 1st in class
    • BH3 mimetic
    • Targets BCL2 interaction → ↓ inhibitory effect on proapoptotic proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage of cancer cells
    • Indications: 
      • CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia
      • AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia

CD20 inhibitors

  • CD20 is a cell surface antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination in B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions and is found in 90% of B-cell neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors.
  • Monoclonal antibodies Monoclonal antibodies Antibodies produced by a single clone of cells. Ebolavirus and Marburgvirus bind BIND Hyperbilirubinemia of the Newborn CD20 and initiate B-cell lysis via complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity Antibody-Dependent Cell-Mediated Cytotoxicity The phenomenon of antibody-mediated target cell destruction by non-sensitized effector cells. The identity of the target cell varies, but it must possess surface immunoglobulin G whose Fc portion is intact. The effector cell is a ‘killer’ cell possessing Fc receptors. It may be a lymphocyte lacking conventional B- or T-cell markers, or a monocyte, macrophage, or polynuclear leukocyte, depending on the identity of the target cell. The reaction is complement-independent. Humoral Adaptive Immunity ( ADCC ADCC The phenomenon of antibody-mediated target cell destruction by non-sensitized effector cells. The identity of the target cell varies, but it must possess surface immunoglobulin G whose Fc portion is intact. The effector cell is a ‘killer’ cell possessing Fc receptors. It may be a lymphocyte lacking conventional B- or T-cell markers, or a monocyte, macrophage, or polynuclear leukocyte, depending on the identity of the target cell. The reaction is complement-independent. Humoral Adaptive Immunity).
  • Related agents:
    • Rituximab Rituximab A murine-derived monoclonal antibody and antineoplastic agent that binds specifically to the cd20 antigen and is used in the treatment of leukemia; lymphoma and rheumatoid arthritis. Immunosuppressants
    • Ofatumumab
    • Obinutuzumab
  • Indications:
    • CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia
    • Non-Hodgkin lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum

Hedgehog pathway inhibitors

  • Hedgehog pathway is involved in cell growth and differentiation.
  • Mutations in the components of the pathway are associated with basal cell carcinoma Basal cell carcinoma Basal cell carcinoma is the most common skin malignancy. This cancer arises from the basal layer of the epidermis. The lesions most commonly appear on the face as pearly nodules, often with telangiectatic blood vessels and ulceration in elderly individuals. Basal Cell Carcinoma (BCC) (uncontrolled proliferation of basal cells in the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions).
  • Inhibitory agents generally bind BIND Hyperbilirubinemia of the Newborn a protein component and inhibit the Hedgehog signal transduction Transduction The transfer of bacterial DNA by phages from an infected bacterium to another bacterium. This also refers to the transfer of genes into eukaryotic cells by viruses. This naturally occurring process is routinely employed as a gene transfer technique. Bacteriology.
  • Related agents:
  • Indication: basal cell carcinoma Basal cell carcinoma Basal cell carcinoma is the most common skin malignancy. This cancer arises from the basal layer of the epidermis. The lesions most commonly appear on the face as pearly nodules, often with telangiectatic blood vessels and ulceration in elderly individuals. Basal Cell Carcinoma (BCC)
  • Adverse effects: birth defects, dermatologic toxicity Toxicity Dosage Calculation

Immune checkpoint inhibitors Immune Checkpoint Inhibitors Drugs that block negative regulator immune checkpoint proteins (e.g., PD-1 receptor and CTLA-4 antigen) thereby increasing suppressed immune activation in immunotherapies. Cancer Immunotherapy

  • Immune checkpoints are normally present to prevent the immune system Immune system The body’s defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs (e.g., T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions) from harming normal cells.
  • With checkpoints present, tumor Tumor Inflammation cells evade immunosurveillance.
  • These drugs allow proliferation and activation of effector T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions by inhibiting immune checkpoints:
    • Programmed cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death 1 ( PD-1 PD-1 An inhibitory t-lymphocyte receptor that has specificity for CD274 antigen and programmed cell death 1 ligand 2 protein. Signaling by the receptor limits T cell proliferation and interferon gamma synthesis. The receptor also may play an essential role in the regulatory pathway that induces peripheral tolerance. T cells: Types and Functions) activity 
    • Cytotoxic Cytotoxic Parvovirus B19 T-lymphocyte antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination 4 (CTLA4)
  • Related agents:
    • Anti-CTLA4 antibody:
      • Ipilimumab
      • Tremelimumab
    • Anti– PD-1 PD-1 An inhibitory t-lymphocyte receptor that has specificity for CD274 antigen and programmed cell death 1 ligand 2 protein. Signaling by the receptor limits T cell proliferation and interferon gamma synthesis. The receptor also may play an essential role in the regulatory pathway that induces peripheral tolerance. T cells: Types and Functions antibody: nivolumab Nivolumab A genetically engineered, fully humanized immunoglobulin g4 monoclonal antibody that binds to the pd-1 receptor, activating an immune response to tumor cells. It is used as monotherapy or in combination with ipilimumab for the treatment of advanced malignant melanoma. It is also used in the treatment of advanced or recurring non-small cell lung cancer; renal cell carcinoma; and Hodgkin’s lymphoma. Melanoma
  • Indications:
    • Colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer
    • Hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases ( HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases)
    • Malignant pleural mesothelioma Mesothelioma Malignant mesothelioma (usually referred to as simply “mesothelioma”) is the malignant growth of mesothelial cells, most commonly affecting the pleura. The majority of cases are associated with occupational exposure to asbestos that occurred > 20 years before clinical onset, which includes dyspnea, chest pain, coughing, fatigue, and weight loss. Malignant Mesothelioma
    • Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
    • NSCLC
    • Renal cell carcinoma Renal cell carcinoma Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma
    • Nivolumab Nivolumab A genetically engineered, fully humanized immunoglobulin g4 monoclonal antibody that binds to the pd-1 receptor, activating an immune response to tumor cells. It is used as monotherapy or in combination with ipilimumab for the treatment of advanced malignant melanoma. It is also used in the treatment of advanced or recurring non-small cell lung cancer; renal cell carcinoma; and Hodgkin’s lymphoma. Melanoma is also used for urothelial carcinoma, Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma, and gastric cancer Gastric cancer Gastric cancer is the 3rd-most common cause of cancer-related deaths worldwide. The majority of cases are from adenocarcinoma. The modifiable risk factors include Helicobacter pylori infection, smoking, and nitrate-rich diets. Gastric Cancer.
  • Adverse effects: immune-related effects (e.g., nephritis, pneumonitis Pneumonitis Human Herpesvirus 6 and 7)

mTOR inhibitors Mtor Inhibitors Immunosuppressants

  • The mTOR mTOR Peutz-Jeghers Syndrome signaling pathway is involved in regulating cell growth, metabolism, and immune cell differentiation.
    • The pathway is abnormally activated in some tumors.
    • Agents inhibit mTOR mTOR Peutz-Jeghers Syndrome serine Serine A non-essential amino acid occurring in natural form as the l-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines; pyrimidines; and other amino acids. Synthesis of Nonessential Amino Acids/threonine kinase activity.
    • Inhibition leads to the halting of the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle, decreasing proliferation.
    • Agents also have antiangiogenic Antiangiogenic Macular Degeneration effects.
  • Related agents (rapamycin analogs (rapalogs)) and indications:
    • Everolimus Everolimus A derivative of sirolimus and an inhibitor of tor serine-threonine kinases. It is used to prevent graft rejection in heart and kidney transplant patients by blocking cell proliferation signals. It is also an antineoplastic agent. Immunosuppressants:
      • Renal cell carcinoma Renal cell carcinoma Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma
      • Prevention of transplant rejection
      • Tuberous sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor complex associated partial-onset seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, renal angiomyolipoma Angiomyolipoma A benign tumor containing vascular, adipose, and muscle elements. It occurs most often in the kidney with smooth muscle elements (angiolipoleiomyoma) in association with tuberous sclerosis. Tuberous Sclerosis, and subependymal giant cell astrocytoma Astrocytoma Astrocytomas are neuroepithelial tumors that arise from astrocytes, which are star-shaped glial cells (supporting tissues of the CNS). Astrocytomas are a type of glioma. There are 4 grades of astrocytomas. Astrocytoma 
      • Neuroendocrine tumors Neuroendocrine tumors Tumors whose cells possess secretory granules and originate from the neuroectoderm, i.e., the cells of the ectoblast or epiblast that program the neuroendocrine system. Common properties across most neuroendocrine tumors include ectopic hormone production (often via apud cells), the presence of tumor-associated antigens, and isozyme composition. Gastrinoma
      • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
    • Temsirolimus Temsirolimus Immunosuppressants: renal cell carcinoma Renal cell carcinoma Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma
    • Sirolimus Sirolimus A macrolide compound obtained from streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to immunophilins. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties. Immunosuppressants
      • Lymphangioleiomyomatosis Lymphangioleiomyomatosis A disease characterized by the progressive invasion of smooth muscle cells into the lymphatic vessels, and the blood vessels. The majority of the cases occur in the lungs of women of childbearing age, eventually blocking the flow of air, blood, and lymph. The common symptom is shortness of breath (dyspnea). Interstitial Lung Diseases 
      • Prevention of transplant rejection
  • Adverse effects: 
    • Serious infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
    • Pulmonary toxicity Toxicity Dosage Calculation
    • Angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. Angioedema
    • ↑ Lipid
    • Secondary malignancy Malignancy Hemothorax

Proteasome inhibitors

  • Proteasomes are complexes that break down proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis into peptides.
    • Generally affect Affect The feeling-tone accompaniment of an idea or mental representation. It is the most direct psychic derivative of instinct and the psychic representative of the various bodily changes by means of which instincts manifest themselves. Psychiatric Assessment different signaling pathways
    • An important effect leading to antineoplastic activity involves nuclear factor kappa B (NF-κB) (bound to IκB).
    • Under cellular stress, NF-κB enters the nucleus Nucleus Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (cell nucleolus). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the endoplasmic reticulum. A cell may contain more than one nucleus. The Cell: Organelles to activate genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure needed for in cell survival
    • Proteasomes degrade IκB to release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology NF-κB.
    • With inhibition of proteasomes, there is increased apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage and decreased survival of cancer cells.
  • Related agents:
    • Bortezomib
    • Carfilzomib
    • Ixazomib
  • Indications: 
    • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma 
    • Bortezomib is also used for mantle cell lymphoma Mantle cell lymphoma A form of non-Hodgkin lymphoma having a usually diffuse pattern with both small and medium lymphocytes and small cleaved cells. It accounts for about 5% of adult non-Hodgkin lymphomas in the United States and Europe. The majority of mantle-cell lymphomas are associated with a t(11; 14) translocation resulting in overexpression of the cyclin D1 gene. Non-Hodgkin Lymphomas.
  • Adverse effects:
    • Cardiotoxicity
    • Myelosuppression Myelosuppression Oxazolidinones
    • Hepatotoxicity Hepatotoxicity Acetaminophen
    • Neuropathy Neuropathy Leprosy
    • Thrombotic microangiopathy
    • Tumor lysis syndrome Tumor lysis syndrome Tumor lysis syndrome is a potentially lethal group of metabolic disturbances that occurs when large numbers of cancer cells are killed rapidly. The lysed cells release their intracellular contents into the bloodstream, resulting in the development of hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute kidney injury. Tumor Lysis Syndrome (TLS)

Thalidomide Thalidomide A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, but withdrawn from the market due to teratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppressive and anti-angiogenic activity. It inhibits release of tumor necrosis factor-alpha from monocytes, and modulates other cytokine action. Immunosuppressants and lenalidomide Lenalidomide Has immunomodulatory (↓ tumor necrosis factor-⍺, ↑ natural killer cells and IL-2) and antiangiogenic activity. Induces cell-cycle arrest and death → inhibiting tumor cell growth. Cancer Immunotherapy

  • Thalidomide Thalidomide A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, but withdrawn from the market due to teratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppressive and anti-angiogenic activity. It inhibits release of tumor necrosis factor-alpha from monocytes, and modulates other cytokine action. Immunosuppressants was originally withdrawn owing to teratogenicity and dysmelia.
  • Found to have immunomodulating activity (↓ tumor Tumor Inflammation necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage factor ɑ, ↑ natural killer cells Natural killer cells A specialized subset of T-lymphocytes that exhibit features of innate immunity similar to that of natural killer cells. They are reactive to glycolipids presented in the context of the major histocompatibility complex (MHC) class I-like molecule, CD1D antigen. Lymphocytes: Histology and interleukin-2 Interleukin-2 A soluble substance elaborated by antigen- or mitogen-stimulated T-lymphocytes which induces DNA synthesis in naive lymphocytes. Interleukins) and antiangiogenic Antiangiogenic Macular Degeneration effects
  • Related agents and indications:
    • Thalidomide Thalidomide A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, but withdrawn from the market due to teratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppressive and anti-angiogenic activity. It inhibits release of tumor necrosis factor-alpha from monocytes, and modulates other cytokine action. Immunosuppressants:
      • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma
      • Erythema nodosum Erythema nodosum Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum leprosum
    • Lenalidomide Lenalidomide Has immunomodulatory (↓ tumor necrosis factor-⍺, ↑ natural killer cells and IL-2) and antiangiogenic activity. Induces cell-cycle arrest and death → inhibiting tumor cell growth. Cancer Immunotherapy:
      • Follicular lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum
      • Mantle cell lymphoma Mantle cell lymphoma A form of non-Hodgkin lymphoma having a usually diffuse pattern with both small and medium lymphocytes and small cleaved cells. It accounts for about 5% of adult non-Hodgkin lymphomas in the United States and Europe. The majority of mantle-cell lymphomas are associated with a t(11; 14) translocation resulting in overexpression of the cyclin D1 gene. Non-Hodgkin Lymphomas
      • Marginal zone lymphoma Marginal zone lymphoma Extranodal lymphoma of lymphoid tissue associated with mucosa that is in contact with exogenous antigens. Many of the sites of these lymphomas, such as the stomach, salivary gland, and thyroid, are normally devoid of lymphoid tissue. They acquire mucosa-associated lymphoid tissue (MALT) type as a result of an immunologically mediated disorder. MALT Lymphoma
      • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma
      • Myelodysplastic syndrome

L-asparaginase

  • Leukemic cells require exogenous asparagine Asparagine A non-essential amino acid that is involved in the metabolic control of cell functions in nerve and brain tissue. It is biosynthesized from aspartic acid and ammonia by asparagine synthetase. Synthesis of Nonessential Amino Acids for growth.
  • L-asparaginase, an enzyme, depletes serum asparagine Asparagine A non-essential amino acid that is involved in the metabolic control of cell functions in nerve and brain tissue. It is biosynthesized from aspartic acid and ammonia by asparagine synthetase. Synthesis of Nonessential Amino Acids (deamidation of asparagine Asparagine A non-essential amino acid that is involved in the metabolic control of cell functions in nerve and brain tissue. It is biosynthesized from aspartic acid and ammonia by asparagine synthetase. Synthesis of Nonessential Amino Acids to aspartic acid and ammonia Ammonia A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. Note that the aqueous form of ammonia is referred to as ammonium hydroxide. Acid-Base Balance).
  • Indication: ALL
  • Adverse effects:
    • Hepatotoxicity Hepatotoxicity Acetaminophen
    • Hemorrhage
    • Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance
    • ↑ Lipid

Comparison of Nontraditional Agents

Table: Nontraditional antineoplastic agents
Drugs Activity
Protein kinase Protein kinase A family of enzymes that catalyze the conversion of ATP and a protein to adp and a phosphoprotein. Interferons inhibitors:
  • BCR-ABL inhibitors
  • BRAF inhibitors
  • MEK inhibitors
  • JAK inhibitors
  • CDK inhibitors
  • BTK inhibitors
  • ALK inhibitors
Inhibit action of protein kinase Protein kinase A family of enzymes that catalyze the conversion of ATP and a protein to adp and a phosphoprotein. Interferons enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
Growth factor receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors inhibitors:
  • EGFR agents
  • VEGFR agents
  • HER2/Neu agents
  • PDGFR agents
PARP inhibitors DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure repair capability
BCL2 inhibitors Promote apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage of cancer cells (which are dependent on this pathway)
CD20 inhibitors Bind BIND Hyperbilirubinemia of the Newborn cell surface antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination and initiate B-cell lysis
Hedgehog pathway inhibitors Bind BIND Hyperbilirubinemia of the Newborn protein component and inhibit the Hedgehog signal transduction Transduction The transfer of bacterial DNA by phages from an infected bacterium to another bacterium. This also refers to the transfer of genes into eukaryotic cells by viruses. This naturally occurring process is routinely employed as a gene transfer technique. Bacteriology, ↓ proliferation of cells (in basal cell carcinoma Basal cell carcinoma Basal cell carcinoma is the most common skin malignancy. This cancer arises from the basal layer of the epidermis. The lesions most commonly appear on the face as pearly nodules, often with telangiectatic blood vessels and ulceration in elderly individuals. Basal Cell Carcinoma (BCC))
Immune checkpoint inhibitors Immune Checkpoint Inhibitors Drugs that block negative regulator immune checkpoint proteins (e.g., PD-1 receptor and CTLA-4 antigen) thereby increasing suppressed immune activation in immunotherapies. Cancer Immunotherapy Inhibit immune checkpoints (CTLA4, PD-1 PD-1 An inhibitory t-lymphocyte receptor that has specificity for CD274 antigen and programmed cell death 1 ligand 2 protein. Signaling by the receptor limits T cell proliferation and interferon gamma synthesis. The receptor also may play an essential role in the regulatory pathway that induces peripheral tolerance. T cells: Types and Functions), allowing activation and proliferation of T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions
mTOR inhibitors Mtor Inhibitors Immunosuppressants Inhibit mTOR mTOR Peutz-Jeghers Syndrome kinase activity, leading to reduced protein synthesis Synthesis Polymerase Chain Reaction (PCR), cell proliferation and angiogenesis Angiogenesis Bartonella
Proteasome inhibitors Block proteasome activity, disrupting signaling and increasing cellular apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage
Asparaginase Asparaginase A hydrolase enzyme that converts l-asparagine and water to l-aspartate and NH3. Acute Lymphoblastic Leukemia Depletes asparagine Asparagine A non-essential amino acid that is involved in the metabolic control of cell functions in nerve and brain tissue. It is biosynthesized from aspartic acid and ammonia by asparagine synthetase. Synthesis of Nonessential Amino Acids, thus reducing source of leukemic cells
Thalidomide Thalidomide A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, but withdrawn from the market due to teratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppressive and anti-angiogenic activity. It inhibits release of tumor necrosis factor-alpha from monocytes, and modulates other cytokine action. Immunosuppressants
  • Immunomodulator
  • Antiangiogenesis

References

  1. Bhullar, K. S., et al. (2018). Kinase-targeted cancer therapies: progress, challenges and future directions. Molecular Cancer 17:48. https://doi.org/10.1186/s12943-018-0804-2
  2. Chu, E. (2021). Cancer chemotherapy. Chapter 54 of Katzung, B.G., Vanderah, T.W. (Eds.), Basic & Clinical Pharmacology, 15th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2988&sectionid=250603422
  3. Cohen, S., Reddy, V. (2021). Janus kinase inhibitors for rheumatologic and other inflammatory disorders: Biology, principles of use and adverse effects. UpToDate. Retrieved Oct 7, 2021, from https://www.uptodate.com/contents/janus-kinase-inhibitors-for-rheumatologic-and-other-inflammatory-disorders-biology-principles-of-use-and-adverse-effects
  4. Katzung, B.G., et al. (Eds.). (2021). Cancer chemotherapy. Chapter 54 of Katzung & Trevor’s Pharmacology: Examination & Board Review, 13th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=3058&sectionid=255307933
  5. Sausville, E.A., Longo, D.L. (2018). Principles of cancer treatment. Chapter 69 of Jameson, J, et al. (Eds.), Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192014984
  6. Thomson, R.J., Moshirfar, M., Ronquillo, Y. (2021). Tyrosine kinase inhibitors. StatPearls. https://www.ncbi.nlm.nih.gov/book,s/NBK563322/
  7. Wellstein, A., Giaccone, G., Atkins, M.B., Sausville, E.A. (2017). Pathway-targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. Chapter 67 of Brunton, L.L., Hilal-Dandan, R., & Knollmann, B.C. (Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=172487438
  8. National Cancer Institute. (2021). Targeted cancer therapies. https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-sheet

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