Notes: Anti-Cancer Drug Mechanisms of Alkylating and Antimetabolite Agents

1. Alkylating Agents

• Mechanism of Action:

  • Alkylating agents add alkyl groups (e.g., methyl, ethyl) to DNA, primarily at the N7 position of guanine.

  • This causes:

    • DNA cross-linking (intra- and inter-strand).

    • Mispairing of bases.

    • DNA strand breakage.

    • Inhibition of DNA replication and transcription → cell death.

  • Cell cycle non-specific (but most toxic to rapidly dividing cells).

• Examples:

  • Cyclophosphamide

  • Melphalan

  • Chlorambucil

  • Busulfan

  • Nitrosoureas (Carmustine, Lomustine)

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2. Antimetabolites

• Mechanism of Action:

  • Structural analogs of normal cellular metabolites (purines, pyrimidines, folic acid).

  • They interfere with DNA/RNA synthesis by:

    • Inhibiting enzymes involved in nucleotide synthesis.

    • Being incorporated into DNA/RNA, leading to chain termination or faulty nucleic acids.

  • S-phase specific (active during DNA synthesis phase).

• Subclasses and Examples:

  • Folic Acid Antagonists:

    • Methotrexate → Inhibits dihydrofolate reductase (DHFR) → ↓ thymidylate/purine synthesis.

  • Pyrimidine Analogues:

    • 5-Fluorouracil (5-FU) → Inhibits thymidylate synthase.

    • Cytarabine → Inhibits DNA polymerase.

  • Purine Analogues:

    • 6-Mercaptopurine (6-MP) → Inhibits IMP conversion to AMP/GMP.

    • Fludarabine, Cladribine → DNA incorporation and polymerase inhibition.

    • 

📝 MCQs: Mechanism of Anti-Cancer Drugs

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1. Which of the following is the primary target of alkylating agents?

A. Topoisomerase
B. DNA polymerase
C. N7 position of guanine in DNA
D. RNA polymerase
✅ Answer: C

2. What is the main mechanism of action of methotrexate?

A. Inhibits DNA polymerase
B. Inhibits thymidylate synthase
C. Inhibits dihydrofolate reductase
D. Causes DNA alkylation
✅ Answer: C

3. Which phase of the cell cycle do antimetabolites primarily act on?

A. G1 phase
B. S phase
C. G2 phase
D. M phase
✅ Answer: B

4. 5-Fluorouracil inhibits which enzyme?

A. Ribonucleotide reductase
B. Dihydrofolate reductase
C. DNA polymerase
D. Thymidylate synthase
✅ Answer: D

5. DNA cross-linking caused by alkylating agents leads to:

A. Increased transcription
B. Enhanced protein synthesis
C. Inhibition of DNA replication
D. Increased RNA stability
✅ Answer: C