Anticancer Drug Classes

Cancer Chemotherapy: Drug Classification and Mechanism of Action



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)

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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)

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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

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  • 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)

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