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Inherited variations in drug-metabolizing enzymes: significance in clinical oncology

L Iyer1

  • 1Department of Medicine and Committee on Clinical Pharmacology, The University of Chicago, Chicago, Illinois 60637, USA. liyer@mcis.bsd.uchicago.edu

Molecular Diagnosis : a Journal Devoted to the Understanding of Human Disease Through the Clinical Application of Molecular Biology
|February 15, 2000
PubMed

Insights

Pharmacogenetics helps explain why cancer patients respond differently to chemotherapy. Genetic variations in drug-metabolizing enzymes significantly impact treatment effectiveness and toxicity for anticancer agents.

Area of Science:

  • Oncology
  • Pharmacogenetics
  • Molecular Biology

Background:

  • Cancer chemotherapy exhibits significant intersubject variability in patient response and toxicity.
  • Genetic differences in enzymes metabolizing anticancer drugs are a key factor in this variability.
  • Anticancer agents like 6-mercaptopurine, 5-fluorouracil, and irinotecan possess a narrow therapeutic index, increasing risks of severe toxicity.

Purpose of the Study:

  • To discuss the impact of genetic polymorphisms in key drug-metabolizing enzymes on the disposition of commonly used anticancer agents.
  • To highlight the role of pharmacogenetics in understanding and potentially mitigating chemotherapy-related toxicities.

Main Methods:

  • Review of existing literature on pharmacogenetics in oncology.
  • Discussion of specific drug-metabolizing enzymes: thiopurine S-methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), and uridine diphosphate glucuronosyltransferase (UGT).
  • Analysis of the influence of polymorphisms in these enzymes on the metabolism and efficacy of anticancer drugs.

Main Results:

  • Polymorphisms in TPMT significantly affect 6-mercaptopurine metabolism, influencing treatment outcomes.
  • DPD deficiency leads to altered 5-fluorouracil disposition, increasing the risk of severe toxicity.
  • UGT polymorphisms impact irinotecan metabolism, affecting its efficacy and toxicity profile.

Conclusions:

  • Pharmacogenetics plays a crucial role in personalizing cancer chemotherapy.
  • Understanding genetic variations in drug-metabolizing enzymes can guide dose adjustments and improve patient safety.
  • Further research in pharmacogenetics is essential for optimizing oncologic treatments.

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