, Volume 3, Issue 3–4, pp 227–253 | Cite as

Antineoplastic and Immunosuppressive Drugs I: Biochemical and Clinical Pharmacological Considerations

  • A. H. Chalmers
  • L. A. Burgoyne
  • A. W. Murray
Review Article


The pharmacokinetic properties of antineoplastic drugs which influence their administration and effects include absorption, plasma protein binding, passage across cell membranes, biotransformation, and excretion through the kidney, hepatobiliary system and the lung.

Some of the drugs can not be given orally while others produce more reliable blood levels if given parenterally. The serum half-life for most drugs is short. Only cyclophosphamide, and prednisone in large doses, cross the blood-brain barrier in significant concentrations. Most of the drugs are metabolised. In the case of cyclophosphamide, biotransformation by hepatic microsomal enzymes is responsible for converting the drug into an active form. A few drugs, like methotrexate, are excreted in the urine as the unchanged parent compound, thus good renal function is essential for the efficient clearance and safe use of the drug.

Although the large range of antineoplastic and immunosuppressive drugs available have widely differing specific sites of action, they all have one effect in common, in that they inhibit cellular proliferation by interferring with nuclear cleavage or by restricting the synthesis of macromolecules (nucleic acids and proteins). To be effective the unchanged drug or its active metabolite(s) must accumulate in the target tumour cell or the cell stimulated to produce antibody.

Alkylating agents (cyclophosphamide, nitrogen mustard, chlorambucil, melphalan and busulphan) alkylate the N-7 position of guanine in DNA, and antibiotics (actinomycin D and daunorubicin) inhibit DNA-dependent RNA synthesis. The enzyme colaspase (L-asparaginase) acts to limit the supply of L-asparagine to tissues unable to synthesise this amino acid, while the vinca alkaloids (vinblastine and vincristine) produce metaphase arrest probably by specific interaction with microtubular protein, a component of the spindle apparatus. The action of the glucocorticoid hormones is not clear, but it is most likely that they act via normal control mechanisms that usually mediate the effect of these hormones. The folic acid antagonist methotrexate limits the synthesis of both purine and pyrimidine nucleotides by inhibiting dihydrofolate reductase. The major site of action of 5-fluorouracil is inhibition of thymidine nucleotide formation (after activation to 5-fluorodeoxyuridylic acid). 6-Mercaptopurine inhibits the utilisation of preformed purines by tissues requiring them. It is also activated to thionucleotide analogues which interfere with the de novo synthesis of purine nucleotides from simple precursors. Cytarabine is activated to its nucleoside triphosphate derivative which then acts to inhibit DNA polymerase.

Because a major biochemical requirement of dividing cells is protein and nucleic acid synthesis, inhibition at any one of the above-mentioned sites is likely to retard proliferation.

Key Words

Antineoplastic drugs: pharmacokinetics Cell proliferation Cytotoxic drugs Immune response 


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Copyright information

© Adis Press 1972

Authors and Affiliations

  • A. H. Chalmers
    • 1
    • 2
  • L. A. Burgoyne
    • 1
    • 2
  • A. W. Murray
    • 1
    • 2
  1. 1.Department of SurgeryUniversity of AdelaideAustralia
  2. 2.School of Biological SciencesFlinders UniversityBedford ParkAustralia

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