Microtubule and Topoisomerase Inhibitors

Microtubule and topoisomerase inhibitors target cellular structures and processes to inhibit cancer cell proliferation. Microtubule inhibitors act on the cytoskeleton, while topoisomerase inhibitors act on an enzyme that is important in DNA replication and transcription. The microtubule system, along with microfilaments and intermediate filaments, form the cellular 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 by creating double- and single-stranded breaks to relieve supercoils. Inhibiting the enzyme causes termination of DNA replication and DNA damage. There are multiple chemotherapeutic agents in each class that commonly produce myelosuppression as an adverse effect.

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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 in eukaryotic 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

Image by Lecturio.

Topoisomerase inhibitors

  • Agents that exert their antineoplastic activity by impairing the enzymes facilitating the untangling and resealing of DNA strands, ultimately preventing replication
  • Topoisomerases:
    • Enzymes that assist in untangling and resealing the DNA strand
    • Replication occurs along the coiled-coil DNA structure → DNA becomes wound about itself
      • Topoisomerase relieves this by cutting the phosphate backbone. 
      • After the backbone is cut (1 or both of the DNA strands), DNA may be unwound.
      • When the tangling is relieved, DNA 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
    • Breast cancer
    • Kaposi sarcoma
  • Adverse effects:
    • Myelosuppression
    • Hypersensitivity
    • Peripheral neuropathy
    • Cutaneous reactions and alopecia 
    • Infusion-related hypertension or hypotension, bradycardia
    • GI toxicity: vomiting, diarrhea
    • Hepatic impairment: increased liver enzymes, bilirubin
    • Extravasation
Structure of paclitaxel

Structure of paclitaxel

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

Docetaxel

  • Indications:
    • Breast cancer
    • Gastric adenocarcinoma
    • Head and neck cancer
    • Non–small cell lung cancer
    • Prostate cancer
  • Adverse effects:
    • Myelosuppression
    • Fluid retention: such as pleural effusion, ascites, cardiac tamponade
    • Hypersensitivity
    • Myocardial toxicity or exacerbation of cardiac dysfunction
    • Peripheral neuropathy
    • GI toxicity: colitis
    • Ocular: such as cystoid macular edema
    • Secondary malignancy 
    • Tumor lysis syndrome

Cabazitaxel

  • Indication: castration-resistant metastatic prostate cancer (prior treatment with docetaxel)
  • Adverse effects:
    • Myelosuppression 
    • GI toxicity: vomiting, diarrhea
    • Peripheral neuropathy
    • Hepatic impairment: ↑ liver enzymes, bilirubin
    • Pulmonary toxicity
    • Urinary: hematuria, cystitis
    • Renal failure

Contraindications and drug interactions

  • Contraindications:
    • 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
    • Kaposi sarcoma
    • Testicular cancer
    • Langerhans cell histiocytosis
  • Adverse effects:
    • Myelosuppression
    • Neurotoxicity: ↓ deep tendon reflexes, paresthesia, vertigo, peripheral neuritis
    • Cardiovascular: hypertension, myocardial ischemia, angina
    • Dermatologic: alopecia, dermatitis
    • Extravasation
    • Pulmonary toxicity: bronchospasm
    • GI toxicity: abdominal pain, diarrhea, nausea, vomiting, stomatitis
    • SIADH

Vincristine

  • Indications:
    • ALL
    • Hodgkin and non-Hodgkin lymphoma
    • Neuroblastoma
    • Rhabdomyosarcoma
    • Wilms tumor
  • Adverse effects:
    • Myelosuppression
    • Neurotoxicity: peripheral neuropathy
    • Alopecia
    • Pulmonary toxicity: bronchospasm
    • Extravasation
    • GI toxicity: paralytic ileus, vomiting, diarrhea, abdominal cramps
    • SIADH
Structure of vincristine

Structure of vincristine

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

Vinorelbine

  • Indications: 
    • Non–small cell lung cancer
    • Other off-label indications include metastatic breast cancer and cervical cancer.
  • Adverse effects:
    • Myelosuppression
    • GI toxicity: paralytic ileus, constipation, intestinal obstruction
    • Hepatotoxicity: ↑ transaminases, bilirubin
    • Peripheral neuropathy
    • Pulmonary toxicity: bronchospasm, ARDS
    • 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 strands → DNA 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 by carboxylesterase enzymes
  • Indications:
    • Advanced colorectal cancer as part of the chemotherapy regimen FOLFIRI (folinic acid, fluorouracil, irinotecan)
    • Also used for off-label indications
  • Adverse effects:
    • Myelosuppression
    • Severe 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/topoisomerase I aggregate → stabilizes cleavable complex, preventing religation of cleaved DNA strand → DNA damage 
  • Indications:
    • Ovarian cancer
    • Small cell 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
  • Drug interactions:
    • Topotecan and granulocyte colony-stimulating factors: 
      • ↑ Pulmonary toxicity/interstitial lung disease
      • ↑ Myelosuppression
    • Irinotecan: 
      • CYP3A4 inhibitors: ↑ active metabolite(s) of irinotecan 
      • 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 to relieve supercoiling.
  • Pharmacodynamics:
    • Inhibit topoisomerase II (which cuts both DNA strands, relieves DNA supercoiling, and religates the DNA strands)
    • Results in DNA 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
    • 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
  • 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

Image by Lecturio.
Table: Comparison of the cell cycle–independent chemotherapy drugs
Drug classMechanism
Antitumor antibiotics:
  • Dactinomycin
  • Mitomycin
Intercalate between bases, leading to blockage of DNA or RNA synthesis and prevention of DNA replication
Anthracyclines
  • Inhibition of topoisomerase II
  • DNA intercalation, leading to DNA and RNA inhibition
  • Promote reactive oxygen species formation
    Alkylating agents
    • ↓ DNA synthesis due to alkylation of DNA
    • ↓ DNA replication, protein synthesis
    Table: Comparison of the cell cycle–dependent chemotherapy drugs
    Drug classCell cycle phase affectedMechanism of action
    AntifolatesCell cycle arrest at S phaseInhibit:
    • Dihydrofolate reductase
    • Thymidylate synthase
    BleomycinCell-cycle arrest at G2 phaseBinds DNA, leading to single- and double-stranded breaks
    FluoropyrimidinesCell cycle arrest at S phaseInhibit thymidylate synthase
    Deoxycytidine analogsCell cycle arrest at S phaseInhibit:
    • DNA polymerase
    • Ribonucleotide reductase
    Purine analogsCell cycle arrest at S phaseInhibition of de novo purine synthesis
    Topoisomerase II inhibitorsCell-cycle arrest at S and G2 phasesInhibit topoisomerase II
    TaxanesCell-cycle arrest at metaphase of the M phaseHyperstabilization of microtubules
    Vinca alkaloidsCell-cycle arrest during metaphase of the M phaseBinds 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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