Cancer Chemotherapy: Cytotoxic Drugs Summary

Introduction

  • Overview of cancer chemotherapy presented by Anand Krishnan, MPharm, PhD.
  • Focus on cytotoxic drugs, including classification, mechanisms, side effects, and mechanisms of resistance.

Learning Objectives

  • Classify cytotoxic drugs.
  • Describe mechanisms of action for different classes of cytotoxic drugs.
  • List major side effects associated with each class of drugs.
  • Discuss resistance mechanisms for drugs in each class.

Classification of Cytotoxic Agents

  • Alkylating Agents: Cross-link DNA.
  • Antimetabolites: Mimic DNA components to inhibit synthesis.
  • Antitumor Antibiotics: Generated from microbes with various mechanisms of action.
  • Plant Alkaloids: Derived from plants, affecting mitosis and DNA topoisomerases.

Alkylating Agents

  • Mechanism of Action:

    • Crosslink DNA through alkylation (covalent bonding with DNA).
    • Targets the N-7 position of Guanine, leading to cell death.

  • Examples:

    1. Cyclophosphamide:
    • Activated to phosphoramide mustard; treats leukemia, lymphomas, breast, and ovarian cancers.
    • Adverse effects: Hemorrhagic cystitis due to acrolein; can reverse with hydration, drug delivery methods, and MESNA.
    • Resistance: Metabolic activation failure.
    1. Nitrosoureas (e.g., lomustine, carmustine):
    • Highly lipophilic, used for brain tumors.
    1. Cisplatin/Carboplatin:
    • Modify DNA and are used in various solid tumors.
    • Adverse effects: Peripheral neuropathy, nephrotoxicity, ototoxicity.

Antimetabolites

  • Mechanism of Action:

    • Cell-cycle specific (S phase); mimic essential structures for DNA synthesis.
    • Inhibit key enzymes necessary for DNA replication.

  • Examples:

    1. Methotrexate:
    • Inhibits DHFR; used in various cancers.
    • Can reverse induced folate deficiency using Leucovorin.
    • Resistance: Defects in cellular uptake; polyglutamylation increases drug retention.
    1. 5-Fluorouracil (5-FU):
    • Converts to 5-fluorinated dUMP, inhibits thymidylate synthase.
    • Adverse effects: Hand-foot syndrome, mucosal ulcers.
    1. Capecitabine:
    • Prodrug of 5-FU; similar adverse effects.

Antitumor Antibiotics

  • Mechanism: Varies through free radical production and DNA modulation.

  • Examples:

    1. Doxorubicin/Daunorubicin:
    • Inhibits topoisomerase II and produces free radicals; cardiotoxicity risk.
    1. Actinomycin D:
    • Intercalates DNA, inhibits RNA polymerase, leading to damage.
    1. Bleomycin:
    • Induces DNA strand breaks; adverse effect includes pulmonary fibrosis.

Plant Alkaloids

  • Mechanism of Action: Affect microtubule dynamics and topoisomerase activity.

  • Examples:

    1. Camptothecins (e.g., Topotecan):
    • Inhibits topoisomerase I; used in various cancers.
    1. Podophyllotoxins (Etoposide):
    • Inhibits topoisomerase II; can cause secondary leukemia.
    1. Vinca Alkaloids (Vincristine/Vinblastine):
    • Prevent microtubule formation; peripheral neuropathy risk.
    1. Taxanes (Paclitaxel):
    • Stabilizes microtubules; adverse effects including neuropathy.

Targeted Therapies

  • Angiogenesis Inhibitors:
    • Target and inhibit VEGF to prevent tumor-associated angiogenesis.
    • Bevacizumab: Monoclonal antibody against VEGF.
    • Sunitinib: Tyrosine kinase inhibitor.

Pro-Apoptotic Agents

  • Assists in Programmed Cell Death:
    • Governed by BCL-2 family proteins; triggers apoptosis via pro-apoptotic substances.
    • Venetoclax: Displaces BCL2, promoting apoptosis in CLL.

Sample Questions

  • Example questions to assess knowledge of drug mechanisms and applications.

References

  • Suggested readings for further understanding, including works by Robert A. Weinberg and resources on pharmacology and cancer.