Targeted and Other Nontraditional Antineoplastic Therapy

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.”

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:
  • The protein kinases Kinases Macrolides and Ketolides function by adding a phosphate group Phosphate group Nucleic Acids to protein substrates: 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, or 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.
  • After 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, the protein undergoes conformational change (“turns the protein on”).
  • Phosphatases Phosphatases Oxazolidinones (which remove phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes) reverse the action of kinases Kinases Macrolides and Ketolides.
• 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 

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
    • Seen in 60% of melanomas and 15% of colorectal cancers
    • Lead to increased tumor Tumor Inflammation survival and mobility
• Related agents (block the activity of mutated BRAF):
  • Vemurafenib
  • Dabrafenib

MEK inhibitors

• Mitogen-activated extracellular kinases Kinases Macrolides and Ketolides (MEKs) are serine-threonine kinases Kinases Macrolides and Ketolides participating in the mitogen-activated protein kinase Protein kinase A family of enzymes that catalyze the conversion of ATP and a protein to adp and a phosphoprotein. Interferons (MAPK) pathway.
• MAPK is activated in melanomas.
• Agents:
  • Trametinib (1st approved)
  • Cobimetinib
  • Binimetinib
  • Selumetinib

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 Arthritis Acute or chronic inflammation of joints. Osteoarthritis)

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 cell proliferation.
• The complex of cyclin D and CDK → phosphorylate the retinoblastoma gene Retinoblastoma Gene Retinoblastoma 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

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)

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 Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum (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

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:
    • Cellular growth
    • Angiogenesis Angiogenesis Bartonella
    • Invasion and metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis
• Monoclonal antibody inhibitors of EGFR:
  • Recognize the extracellular domain of EGFR, leading to:
    • Blocking of ligand binding
    • Recruitment Recruitment Skeletal Muscle Contraction of immune cells, producing an immune response
  • 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)

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 

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

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 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

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 Basal Cell Erythema Multiforme carcinoma (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:
  • Vismodegib Vismodegib Basal Cell Carcinoma (BCC)
  • Sonidegib
  • Glasdegib
• Indication: basal cell Basal Cell Erythema Multiforme carcinoma
• 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 Effector T cells Adaptive Cell-mediated Immunity 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 Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum, 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 mTOR Peutz-Jeghers Syndrome inhibitors

• 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 Subependymal Giant Cell Astrocytoma 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 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 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 Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum.
• Adverse effects:
  • Cardiotoxicity
  • Myelosuppression Myelosuppression Oxazolidinones
  • Hepatotoxicity Hepatotoxicity Acetaminophen
  • Neuropathy Neuropathy Leprosy
  • Thrombotic microangiopathy
  • Tumor lysis Tumor Lysis Tumor Lysis Syndrome 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 Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Chalazion 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 Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum
    • Marginal zone Marginal zone MALT Lymphoma lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum
    • 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