Polyfunctional Alkylating Drugs: Mechanism of Action:

Example: Cyclophosphamide:most useful alkylating agent at present.

• Alkyl group transfer
  • Major interaction: Alkylation of DNA

Pharmacological Effects: Polyfunctional Alkylating Drugs

• Injection site damage (vesicant effects) and systemic toxicity.
•  Toxicity:
  • dose related
  • primarily affecting rapidly dividing cells
    • bone marrow
    • GI tract
      •  nausea and vomiting within less than an hour-- with mechlorethamine, carmustine (BCNU) or cyclophosphamide
      • Emetic effects: CNS
        • reduced by pre-treatment with phenothiazines or cannabinoids.
    • gonads
  •  cyclophosphamide cytotoxicity depends on activation by microsomal enzyme system.
    • Hepatic microsomal P450 mixed-function oxidase catalyzes conversion of cyclophosphamide to the active forms:
      • 4-hydroxycyclophosphamide
      • aldophosphamide
  •  Major Toxicity: bone marrow suppression
    • dose-related suppression of myelopoiesis: primary effects on
      • megakaryocytes
      • platelets
      • granulocytes
    • Bone marrow suppression is worse when alkylating agents are combined with other myelosuppressive drugs and/or radiation (does reduction required)
    • If bone marrow suppression is severe, treatment may have to be suspended and then re-initiated upon hematopoietic recovery.
    • Long-term consequences of alkylating agent treatment include:
      • ovarian failure (common)
      • testicular failure (common)
      • acute leukemia (rare)

• Oral Route of Administration: cyclophosphamide, melphalan, chlorambucil, busulfan, lomustine (CCNU)