Cancer Chemotherapy: Drug Classification and Mechanism of Action

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Polyfunctional alkylating agents

  • Common Structural Features:

    • Bis(chloroethyl)amine

    • Ethylenimine

    • Nitrosoureas

    Not cell-cycle specific: Cells most susceptible in late G1 and S phase-- Blocks in G2

  • Most useful agents:

    • Cyclophosphamide (Cytoxan)

      • fosfamide

    • Mechlorethamine

    • Melphalan (Alkeran)

    • Chlorambucil (Leukeran)

  • Secondary agents

    • Thiopeta (Thioplex)

      • Ovarian cancer

    • Busulfan (Myleran)

      • Chronic myeloid leukemia


Major nitrosoureas:

  • Carmustine (BCNU)

  • Lomustine (CCNU)

  • Semustine (methyl CCNU)


Polyfunctional Alkylating Drugs: Mechanism of Action:

  • Alkyl group transfer

    • Major interaction: Alkylation of DNA

      • Primary DNA alkylation site: N7 position of guanine (other sites as well)

      • Interaction may involve single strands or both strands (cross linking, due to bifunctional [2 reactive centers] characteristics)

    • Other interactions: these drugs react with carboxyl, sulfhydryl, amino, hydroxyl, and phosphate groups of other cellular constituents

    • These drugs usually form a reactive intermediate -- ethyleneimonium ion

Polyfunctional Alkylating Drug Resistance

  • Increased ability to repair DNA defects

  • Decreased cellular permeability to the drug

  • Increased glutathione synthesis

    • Inactivates alkylating agents through conjugation reactions (catalyzed by glutathione S-transferase)


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 (dose 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 (Cytoxan), melphalan (Alkeran), chlorambucil (Leukeran), busulfan (Myleran), lomustine (CCNU,CeeNU).

  • Cyclophosphamide (Cytoxan): most useful alkylating agent at present.

  • Busulfan (Myleran): specificity for granulocytes -- chronic myelogenous leukemia

  • Nitrosoureas:

    • Not cross reactive ( with respect to tumor resistance) with other alkylating drugs.

    • Nonenzymatic by transformation required to activate compounds.

    • Highly lipid- soluble-- crosses the blood-brain barrier (BBB)

      • Useful in treating brain tumors

    • Act by cross-linking: DNA alkylation

    • More effective against cells in plateau phase than cells in exponential growth phase

    • Major route of elimination:urinary excretion

    • Steptozocin:

      • Sugar-containing nitrosourea

      • Minimal bone marrow suppression

      • Effective in insulin-secreting islet cell pancreatic carcinoma and sometimes in non-Hodgkin's lymphoma


Other Alkylating Drugs

  • Procarbazine (Matulane)

    • Methylhydrazine derivative

    • Active in Hodgkin's disease (combination therapy)

    • Teratogenic, mutagenic, leukemogenic.

    • Side effects:

      • Nausea, vomiting, myelosuppression

      • Hemolytic anemia

      • Pulmonary effects

  • Dacarbazine (DTIC)

    • Clinical use:

      • Melanoma

      • Hodgkin's disease

      • Soft tissue sarcoma

    • Synthetic drug; requires activation by liver microsomal system.

    • Parenteral administration

    • Side effects:

      • Nausea, vomiting, myelosuppression

  • Altretamine (Hexalen)

    • Clinical use:

      • Alkylating agent-resistant: ovarian carcinoma

    • Activated by biotransformation (demethylation)

    •  Side effects:

      • Nausea, vomiting, central and peripheral nervous system neuropathies.

      • Relatively mild myelosuppressive effects.

  • Cisplatin (Platinol)

    • Clinical use:

      • Genitourinary cancers

        • Testicular

        • Ovarian

        • Bladder

      • In combination with bleomycin and vinblastine: curative treatment for nonseminomatous testicular cancer

      • Carboplatin (less GI and renal toxicity; with myelosuppressive toxicity): alternative to cisplatin

    • Inhibits DNA synthesis; cross-linking; guanine N7 site

    • Platinum compounds: synergistic with other anticancer agents

    • Site effects:

      • Major acute effect: nausea, vomiting

      • Relatively little bone marrow effects

      • Significant renal dysfunction (minimized by adequate hydration/diuretics)

      • Acoustic nerve dysfunction


 Alkylating Agent Toxicity: Summary

  • IV mechlorethamine, cyclophosphamide, carmustine: Nausea and Vomiting (common).

  • Oral cyclophosphamide: Nausea and Vomiting (less frequently).

  •  Most Important Toxic Effect:Bone marrow suppression, leukopenia, thrombocytopenia

    • Secondary to myelosuppression --

      • Severe infection

      • Septicemia

    • Hemorrhage

  • Cyclophosphamide (Cytoxan):alopecia, hemorrhagic cystitis (may be avoided by adequate hydration)

Salmon, S. E. and Sartorelli, A. C. Cancer Chemotherapy, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 881-911.


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