19 In-depth Notes on Chemotherapy Drugs and Mechanisms

Introduction to Chemotherapy Drugs

  • Overview of chemotherapy drugs and their modes of action

Learning Outcomes

  • Fluoro-uracil: Understand its therapeutic role as an antimetabolite due to fluorine content.
  • Tamoxifen: Insight into its function as a select estrogen receptor modulator (SERM).
  • Monoclonal Antibodies: Overview of their therapeutic applications.
  • Combination Therapy (R-CHOP): Familiarity with its components and uses.

Alkylating Agents

  • Chlormethine

    • Mechanism: SN2 process (nucleophile and electrophile interaction).
    • Forms crosslinked DNA, enhancing reactivity.
    • Key Points:
    • Aziridine's ring strain increases nucleophilicity.
    • Cl- treated for clarity during explanations.

  • Chlormethine Analogues

    • Mechanisms:
    • Incorporation of electron-withdrawing aromatic rings reduces nucleophilicity of alkylating agents, leading to fewer side reactions and toxicity.
    • Example drugs: Melphalan, Chloroambucil.

Effect of DNA Alkylation

  • Consequences of alkylated bases on DNA pairing.
    • Guanine's preference for keto tautomer.
    • Abnormal pairing with alkylated guanine (enol tautomer).

Pro-drug Alkylating Agents

  • Cyclophosphamide:

    • Most used alkylating agent; orally active and initially non-toxic.
    • Toxicity linked to acrolein by-product.

  • Nitrosoureas:

    • Decompose in the body to form reactive alkylating agents.
    • Not needed to understand the mechanism.

  • Busulfan:

    • Synthetic anticancer agent; causes DNA interstrand crosslinking via SN2 reaction.

  • Mitomycin C:

    • Activated prodrug; highly toxic with a specific mechanism involving DNA alkylation.

  • CC1065 – Duocarmycin:

    • Natural agent targeting adenine bases with high potency.

Tamoxifen: Estrogen Antagonist

  • Mechanism: Binds to estrogen receptors, blocking estradiol's effect and preventing coactivator binding, making it a partial agonist.
  • Application: Used to treat estrogen-dependent breast cancers.

Antimetabolites: 5-Fluorouracil (5-FU)

  • 5-FU's Role:
    • Mimics uracil; inhibits thymidine biosynthesis due to presence of fluorine.

Monoclonal Antibodies

  • Function: Target tumor-specific antigens; engage immune systems to kill cancer cells.
  • Common applications: Breast, colorectal cancers, and lymphomas.
  • Mechanism involves:
    • Activation of the immune response through binding.

Specific Monoclonal Antibodies

  • Herceptin: Targets HER-2 receptor; used for HER-2 positive breast cancer.
  • Rituximab: Targets CD20 on B cells; utilized for treating lymphomas and leukemias.

Combination Therapies

  • R-CHOP Regimen:
    • FDA-approved for Non-Hodgkin’s lymphoma in 2006; comprises Rituximab, Cyclophosphamide, Vincristine, and Doxorubicin.
    • Usually involves 6–8 treatments, spaced every 21 days.

Appendix 1: Enzymatic Action & Drug Mechanisms

  • Thymidylate Synthase: Catalyzes conversion of dUMP to dTMP.
  • 5-FU Mechanism: Inhibits thymidylate synthase, preventing DNA synthesis due to alkylation prevention by fluorine.