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)