Microtubule and Topoisomerase Inhibitors

Microtubule and topoisomerase inhibitors target cellular structures and processes to inhibit cancer cell proliferation. Microtubule inhibitors act on the cytoskeleton Cytoskeleton A cell's cytosol is the liquid inside the cell membrane that surrounds the organelles and cytoskeleton. The cytosol is a complex solution where many biochemical processes take place. The Cell: Cytosol and Cytoskeleton, while topoisomerase inhibitors act on an enzyme that is important in DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication and 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. The microtubule system, along with microfilaments and intermediate filaments, form the cellular cytoskeleton Cytoskeleton A cell's cytosol is the liquid inside the cell membrane that surrounds the organelles and cytoskeleton. The cytosol is a complex solution where many biochemical processes take place. The Cell: Cytosol and Cytoskeleton. These components are essential for cell division, movement, and signaling. Taxanes and vinca alkaloids interfere with microtubule function, and thus in effect, inhibit mitosis. Topoisomerase assists DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication by creating double- and single-stranded breaks to relieve supercoils. Inhibiting the enzyme causes termination of DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication and DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure damage. There are multiple chemotherapeutic agents in each class that commonly produce myelosuppression as an adverse effect.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Microtubule inhibitors

  • Chemotherapy agents that interfere with the microtubule system, impairing the cellular mitosis, and disrupting the cell shape and motility
  • Microtubule system:
    • Microtubules are a part of the cytoskeleton Cytoskeleton A cell's cytosol is the liquid inside the cell membrane that surrounds the organelles and cytoskeleton. The cytosol is a complex solution where many biochemical processes take place. The Cell: Cytosol and Cytoskeleton in eukaryotic Eukaryotic Eukaryotes can be single-celled or multicellular organisms and include plants, animals, fungi, and protozoa. Eukaryotic cells contain a well-organized nucleus contained by a membrane, along with other membrane-bound organelles. Cell Types: Eukaryotic versus Prokaryotic cells and have multiple functions:
      • Dynamic structures that anchor on centriole near nucleus
      • Directional growth: addition and subtraction of tubulin subunits
      • Highways for transportation within cell by molecular motors
      • Assemble and provide framework for chromosome movement during cell division or mitosis
    • Alpha- and beta-tubulin are the primary components of microtubules.
  • Antineoplastic agents in this class:
    • Taxanes
    • Vinca alkaloids
Filaments of the cytoskeleton

Filaments of the cytoskeleton Cytoskeleton A cell's cytosol is the liquid inside the cell membrane that surrounds the organelles and cytoskeleton. The cytosol is a complex solution where many biochemical processes take place. The Cell: Cytosol and Cytoskeleton

Image by Lecturio.

Topoisomerase inhibitors

  • Agents that exert their antineoplastic activity by impairing the 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 facilitating the untangling and resealing of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure strands, ultimately preventing replication
  • Topoisomerases:
    • Enzymes that assist in untangling and resealing the DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure strand
    • Replication occurs along the coiled-coil DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure structure → DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure becomes wound about itself
      • Topoisomerase relieves this by cutting the phosphate backbone. 
      • After the backbone is cut (1 or both of the DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure strands), DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure may be unwound.
      • When the tangling is relieved, DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure is resealed, or religated.
    • Types:
      • Type I topoisomerase: introduces single-stranded breaks
      • Type II topoisomerase: makes double-stranded breaks
  • Many pharmaceuticals prevent topoisomerase activity, which ultimately leads to cellular death.
    • Fluoroquinolone antibiotics inhibit bacterial topoisomerase activity.
    • This mechanism is also a tool in anticancer medications.
  • Chemotherapeutic agents in this class:
    • Topoisomerase I inhibitors: 
      • Irinotecan
      • Topotecan
    • Topoisomerase II inhibitors: 
      • Etoposide
      • Teniposide
      • Anthracyclines (e.g., doxorubicin)

Taxanes

Description

  • Antineoplastic agents were originally isolated from the bark of a yew tree (Taxus brevifolia); newer agents were subsequently derived semisynthetically.
  • Pharmacodynamics:
    • Taxanes disrupt microtubule functioning.
    • Microtubules are essential parts of mitotic spindles and the axonal structures of nerves.
    • Thus, effect includes inhibition of mitosis, but also adversely leads to axonal damage (neuropathy)
    • Taxanes are considered radiosensitizing medications.
  • Pharmacokinetics:
    • About 90% protein-bound
    • Metabolism: hepatic P450 system
    • Excretion: hepatobiliary route eventually excreted in the feces
  • Medications in this drug class:
    • Paclitaxel (natural product)
    • Docetaxel (semisynthetic analog)
    • Cabazitaxel (semisynthetic analog)

Paclitaxel

  • Indications:
    • 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
    • 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
    • Kaposi sarcoma
  • Adverse effects:
    • Myelosuppression
    • Hypersensitivity
    • Peripheral neuropathy
    • Cutaneous reactions and alopecia Alopecia Alopecia is the loss of hair in areas anywhere on the body where hair normally grows. Alopecia may be defined as scarring or non-scarring, localized or diffuse, congenital or acquired, reversible or permanent, or confined to the scalp or universal; however, alopecia is usually classified using the 1st 3 factors. Alopecia 
    • Infusion-related 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 or hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, bradycardia
    • GI toxicity: vomiting, 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
    • Hepatic impairment: increased liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver 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, bilirubin
    • Extravasation
Structure of paclitaxel

Structure of paclitaxel

Image: “Taxol” by Calvero. License: Public Domain

Docetaxel

  • 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 adenocarcinoma
    • Head and neck cancer
    • 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
    • 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
  • Adverse effects:
    • Myelosuppression
    • Fluid retention: such as pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion, ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites, cardiac tamponade Cardiac tamponade Pericardial effusion is the accumulation of excess fluid in the pericardial space around the heart. The pericardium does not easily expand; thus, rapid fluid accumulation leads to increased pressure around the heart. The increase in pressure restricts cardiac filling, resulting in decreased cardiac output and cardiac tamponade. Pericardial Effusion and Cardiac Tamponade
    • Hypersensitivity
    • Myocardial toxicity or exacerbation of cardiac dysfunction
    • Peripheral neuropathy
    • GI toxicity: colitis
    • Ocular: such as cystoid macular 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
    • Secondary malignancy 
    • 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

Cabazitaxel

  • Indication: castration-resistant metastatic prostate cancer (prior treatment with docetaxel)
  • Adverse effects:
    • Myelosuppression 
    • GI toxicity: vomiting, 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
    • Peripheral neuropathy
    • Hepatic impairment: ↑ liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver 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, bilirubin
    • Pulmonary toxicity
    • Urinary: hematuria, cystitis
    • Renal failure

Contraindications and drug interactions

  • Contraindications:
    • 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:
      • Neutrophil counts < 1500/mm3
      • In Kaposi sarcoma: neutrophil counts < 1000/mm3
    • Previous hypersensitivity reaction
  • Drug interactions: 
    • Anthracyclines: Increases cardiotoxicity
    • CYP3A4 inhibitors (↑ levels of taxane medications) include:
      • Ketoconazole 
      • Erythromycin
      • Clarithromycin 
      • Diltiazem
    • ↓ Therapeutic effects of vaccines (live and inactivated)
    • ↑ Toxic effects of live vaccines

Vinca Alkaloids

Description

  • Agents that inhibit mitosis by disrupting assembly of microtubules
  • Derived from periwinkle plant Vinca rosea
  • Pharmacodynamics:
    • Inhibit tubulin polymerization
      • Suppress microtubule movement at low concentrations
      • Reduce polymer mass of microtubules at higher concentrations
      • At either concentration, lead to mitotic arrest in metaphase
    • Prevent cancer cell division
  • Pharmacokinetics:
    • Metabolism: hepatic, through CYP3A
    • Poor blood–brain barrier penetration
    • Excretion: hepatobiliary system (feces)
  • Medications in this drug class:
    • Vinblastine 
    • Vincristine 
    • Vinorelbine

Vinblastine

  • Indications:
    • Hodgkin and non- 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
    • Kaposi sarcoma
    • Testicular cancer Testicular cancer Testicular cancer is the most common solid malignancy affecting men 15-35 years of age. Most of the testicular cancers are of the germ cell tumor type, and they can be classified as seminomas and nonseminomas. The most common presentation of testicular cancer is a painless testicular mass. Testicular Cancer
    • Langerhans cell histiocytosis
  • Adverse effects:
    • Myelosuppression
    • Neurotoxicity: ↓ deep tendon reflexes, paresthesia, vertigo Vertigo Vertigo is defined as the perceived sensation of rotational motion while remaining still. A very common complaint in primary care and the ER, vertigo is more frequently experienced by women and its prevalence increases with age. Vertigo is classified into peripheral or central based on its etiology. Vertigo, peripheral neuritis
    • Cardiovascular: 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, myocardial ischemia, angina
    • Dermatologic: alopecia Alopecia Alopecia is the loss of hair in areas anywhere on the body where hair normally grows. Alopecia may be defined as scarring or non-scarring, localized or diffuse, congenital or acquired, reversible or permanent, or confined to the scalp or universal; however, alopecia is usually classified using the 1st 3 factors. Alopecia, dermatitis
    • Extravasation
    • Pulmonary toxicity: bronchospasm
    • GI toxicity: abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, 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, vomiting, stomatitis Stomatitis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis
    • SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

Vincristine

  • Indications:
    • ALL
    • Hodgkin and non- 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
    • Neuroblastoma Neuroblastoma Neuroblastoma is a malignancy that arises from the neural crest cell derivatives along the sympathetic chain (neuroblasts) and is most commonly located in the adrenal medulla. The tumor often presents in childhood with a flank mass that crosses the midline. Neuroblastoma
    • Rhabdomyosarcoma
    • Wilms tumor Wilms tumor Wilms tumor is a malignancy caused by proliferation of metanephric blastema in the kidneys and is the most common renal malignancy in children. Wilms tumor usually arises sporadically, but it can also occur as a result of a specific congenital anomaly like WAGR syndrome, Denys-Drash syndrome, or Beckwith-Wiedemann syndrome. Wilms tumor commonly presents as a firm, nontender, smooth mass that does not cross the midline. Wilms Tumor
  • Adverse effects:
    • Myelosuppression
    • Neurotoxicity: peripheral neuropathy
    • Alopecia
    • Pulmonary toxicity: bronchospasm
    • Extravasation
    • GI toxicity: paralytic ileus, vomiting, 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, abdominal cramps
    • SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
Structure of vincristine

Structure of vincristine

Image: “Vincristine” by Fvasconcellos. License: Public Domain

Vinorelbine

  • Indications: 
    • 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
    • Other off-label indications include metastatic breast cancer and 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.
  • Adverse effects:
    • Myelosuppression
    • GI toxicity: paralytic ileus, constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation, intestinal obstruction
    • Hepatotoxicity: ↑ transaminases, bilirubin
    • Peripheral neuropathy
    • Pulmonary toxicity: bronchospasm, ARDS ARDS Acute respiratory distress syndrome is characterized by the sudden onset of hypoxemia and bilateral pulmonary edema without cardiac failure. Sepsis is the most common cause of ARDS. The underlying mechanism and histologic correlate is diffuse alveolar damage (DAD). Acute Respiratory Distress Syndrome
    • SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

Contraindications and drug interactions

  • Contraindications:
    • Severe myelosuppression
    • Active bacterial infection
    • Vincristine: demyelinating form of Charcot-Marie-Tooth syndrome
  • Drug interactions:
    • CYP3A4 inhibitors: ↑ drug concentration of vinca alkaloids
    • ↓ Therapeutic effects of vaccines (live and inactivated)
    • ↑ Toxic effects of live vaccines

Topoisomerase I Inhibitors

Description

  • Topoisomerase I inhibitors are derived from the tree Camptotheca acuminata.
  • Pharmacodynamics:
    • Inhibit the enzyme, topoisomerase I
    • Inhibit topoisomerase I → no enzyme to cut and religate single DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure strands → DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure damage
  • Pharmacokinetics:
    • Dosage forms depend on the medication, but in general has IV and oral forms.
    • Metabolism: hepatic
    • Excretion: renal
  • Medications in this drug class:
    • Irinotecan
    • Topotecan

Irinotecan

  •  A prodrug converted to SN-38 (the active metabolite that inhibits topoisomerase I) in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver by carboxylesterase 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
  • Indications:
    • Advanced 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 as part of the chemotherapy regimen FOLFIRI (folinic acid, fluorouracil, irinotecan)
    • Also used for off-label indications
  • Adverse effects:
    • Myelosuppression
    • Severe 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:
      • Early (< 24 hours): cholinergic effect that can be treated with atropine
      • Late (2–10 days): more severe and can lead to electrolyte abnormality 
    • Pulmonary toxicity
    • Nephrotoxicity
    • Thromboembolism
    • Extravasation
Structure of irinotecan

Structure of irinotecan

Image: “Irinotecan” by Fvasconcellos. License: Public Domain

Topotecan

  • Binds DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure/topoisomerase I aggregate → stabilizes cleavable complex, preventing religation of cleaved DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure strand → DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure damage 
  • Indications:
    • 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
    • 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
    • Cervical cancer
  • Adverse effects:
    • Myelosuppression
    • Diarrhea (similar to irinotecan)
    • Pulmonary toxicity
    • ↑ Transaminases, bilirubin
    • Neutropenic enterocolitis
    • Extravasation

Contraindications and drug interactions

  • Contraindications:
    • Hypersensitivity to drug
    • Severe myelosuppression
    • Severe renal impairment
    • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
  • Drug interactions:
    • Topotecan and granulocyte colony-stimulating factors: 
      • ↑ Pulmonary toxicity/interstitial lung disease
      • ↑ Myelosuppression
    • Irinotecan: 
      • CYP3A4 inhibitors: ↑ active metabolite(s) of irinotecan 
      • Azoles Azoles Azoles are a widely used class of antifungal medications inhibiting the production of ergosterol, a critical component in the fungal cell membrane. The 2 primary subclasses of azoles are the imidazoles, older agents typically only used for topical applications, and the triazoles, newer agents with a wide spectrum of uses. Azoles: ↑ active metabolite(s) of irinotecan
    • ↓ Therapeutic effects of vaccines (live and inactivated)
    • ↑ Toxic effects of live vaccines
Structure of topotecan

Structure of topotecan

Image: “Topotecan” by Fvasconcellos. License: Public Domain

Topoisomerase II Inhibitors

Description

  • Topoisomerase II introduces a double-stranded break in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure to relieve supercoiling.
  • Pharmacodynamics:
    • Inhibit topoisomerase II (which cuts both DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure strands, relieves DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure supercoiling, and religates the DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure strands)
    • Results in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure damage
  • Pharmacokinetics:
    • Available in IV and oral formulations
    • Metabolism: hepatic
    • Excretion: renal (etoposide), feces through biliary excretion (anthracyclines)
    • Medications:
      • Anthracyclines
      • Etoposide
      • Teniposide

Etoposide

  • Indications:
    • 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
    • Testicular cancer Testicular cancer Testicular cancer is the most common solid malignancy affecting men 15-35 years of age. Most of the testicular cancers are of the germ cell tumor type, and they can be classified as seminomas and nonseminomas. The most common presentation of testicular cancer is a painless testicular mass. Testicular Cancer
  • Adverse effects:
    • Myelosuppression
    • Alopecia
    • Hypotension (with rapid infusion)
    • Extravasation
    • Secondary malignancies
  • Contraindications:
    • Hypersensitivity to the drug
    • Severe myelosuppression
    • Severe renal impairment
    • Severe hepatic impairment
  • Drug interactions:
    • Etoposide: ↑ anticoagulant effect of vitamin K antagonists (e.g., warfarin)
    • ↓ Therapeutic effects of vaccines (live and inactivated)
    • ↑ Toxic effects of live vaccines
Structure of etoposide

Structure of etoposide

Image: “Etoposide” by Fvasconcellos. License: Public Domain

Teniposide

  • Indication: acute lymphoblastic leukemia Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia/lymphoma (ALL/LBL) are hematologic malignancies characterized by the uncontrolled proliferation of lymphoid precursor cells. Acute lymphoblastic leukemia/lymphoma, the most common forms of cancer affecting children, show the presence of increased lymphoblasts. Acute Lymphoblastic Leukemia
  • Adverse effects:
    • Myelosuppression
    • Alopecia
    • Diarrhea, nausea, vomiting
    • Extravasation
    • Hypotension (with rapid infusion)
  • Contraindication: hypersensitivity to the drug
  • Drug interactions:
    • May increase neurotoxic effects of vincristine
    • ↓ Therapeutic effects of vaccines (live and inactivated)
    • ↑ Toxic effects of live vaccines

Comparison with Other Chemotherapeutic Agents

Chemotherapy comparison

Various chemotherapy drugs and their effects on 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

Image by Lecturio.
Table: Comparison 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–independent chemotherapy drugs
Drug class Mechanism
Antitumor antibiotics Antitumor Antibiotics Antitumor antibiotics, also known as antineoplastic antibiotics, are the product of soil microbes, Streptomyces bacteria. The commonly used types of antitumor antibiotics (bleomycin, dactinomycin, and anthracyclines) have a wide spectrum of activity against hematologic malignancies and solid tumors. Antitumor Antibiotics:
  • Dactinomycin
  • Mitomycin
Intercalate between bases, leading to blockage of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure or RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure synthesis and prevention of DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication
Anthracyclines
  • Inhibition of topoisomerase II
  • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure intercalation, leading to DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure and RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure inhibition
  • Promote reactive oxygen species formation
Alkylating agents
  • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure synthesis due to alkylation of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure
  • DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication, protein synthesis
Table: Comparison 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–dependent chemotherapy drugs
Drug class Cell cycle phase affected Mechanism of action
Antifolates Cell cycle arrest at S phase Inhibit:
  • Dihydrofolate reductase
  • Thymidylate synthase
Bleomycin Cell-cycle arrest at G2 phase Binds DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure, leading to single- and double-stranded breaks
Fluoropyrimidines Cell cycle arrest at S phase Inhibit thymidylate synthase
Deoxycytidine analogs Cell cycle arrest at S phase Inhibit:
  • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure polymerase
  • Ribonucleotide reductase
Purine analogs Cell cycle arrest at S phase Inhibition of de novo purine synthesis
Topoisomerase II inhibitors Cell-cycle arrest at S and G2 phases Inhibit topoisomerase II
Taxanes Cell-cycle arrest at metaphase of the M phase Hyperstabilization of microtubules
Vinca alkaloids Cell-cycle arrest during metaphase of the M phase Binds to beta-tubulin and prevents microtubule polymerization

References

  1. Chu, E. (2021). Cancer chemotherapy. Chapter 54 in Katzung B. G., Vanderah T. W. (Eds.),  Basic & Clinical Pharmacology, 15th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2988&sectionid=250603422
  2. Lu, Y., Chen, J., Xiao, M., Li, W., Miller, D. (2012). An overview of tubulin inhibitors that interact with the colchicine binding site. Pharm Res 29, pp. 2943–2971. doi.org/10.1007/s11095-012-0828-z
  3. Mukhtar, E., Adhami, V.M., Mukhtar, H. (2014). Targeting microtubules by natural agents for cancer therapy. Mol Cancer Ther 13, pp. 275–284. doi.org/10.1158/1535-7163.MCT-13-0791
  4. Parker, A. L. (2014). Microtubules and their role in cellular stress in cancer. Frontiers. https://www.frontiersin.org/articles/10.3389/fonc.2014.00153/full
  5. Perez, E.A. (2009). Microtubule inhibitors: differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance. Mol Cancer Ther 8, pp. 2086–95. doi.org/10.1158/1535-7163.MCT-09-0366
  6. Cabazitaxel (2021). UpToDate. Retrieved September 25, 2021, from https://www.uptodate.com/contents/cabazitaxel-drug-information
  7. Docetaxel (2021). UpToDate. Retrieved September 25, 2021, from https://www.uptodate.com/contents/docetaxel-drug-information
  8. Etoposide (2021). UpToDate. Retrieved September 26, 2021, from https://www.uptodate.com/contents/etoposide-drug-information
  9. Irinotecan (2021). UpToDate. Retrieved September 26, 2021, from https://www.uptodate.com/contents/irinotecan-conventional-drug-information
  10. Paclitaxel (2021). UpToDate. Retrieved September 24, 2021, from https://www.uptodate.com/contents/paclitaxel-conventional-drug-information
  11. Teniposide (2021). UpToDate. Retrieved September 26, 2021, from https://www.uptodate.com/contents/teniposide-drug-information
  12. Topotecan (2021). UpToDate. Retrieved September 26, 2021, from https://www.uptodate.com/contents/topotecan-drug-information
  13. Vinblastine (2021). UpToDate. Retrieved September 25, 2021, from https://www.uptodate.com/contents/vinblastine-drug-information
  14. Vincristine (2021). UpToDate. Retrieved September 25, 2021, from https://www.uptodate.com/contents/vincristine-conventional-drug-information
  15. Vinorelbine (2021). UpToDate. Retrieved September 25, 2021, from https://www.uptodate.com/contents/vinorelbine-drug-information

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