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Role of pharmacogenetics in irinotecan therapy.

Abstract
In the treatment of advanced colorectal cancer, irinotecan has become one of the most important drugs, despite its sometimes unpredictable adverse effects. To understand why some patients experience severe adverse effects (diarrhea and neutropenia), while others do not, the metabolic pathways of this drug have to be unraveled in detail. Individual variation in expression of several phase I and phase II metabolizing enzymes and ABC-transporters involved in irinotecan metabolism and excretion, at least partly explains the observed pharmacokinetic interpatient variability. Although the difference in expression-level of these proteins to a certain amount is explained by physiologic and environmental factors, the presence of specific genetic determinants also does influence their expression and function. In this review, the role of genetic polymorphisms in the main enzyme-systems (carboxylesterase, cytochrome P450 3A, and uridine diphosphate-glucuronosyltransferase) and ABC-transporters (ABCB1, ABCC2, and ABCG2) involved in irinotecan metabolism, are discussed. Since at this moment the field of pharmacogenetics and pharmacogenomics is rapidly expanding and simultaneously more rapid and cost-effective screening methods are emerging, a wealth of future data is expected to enrich our knowledge of the genetic basis of irinotecan metabolism. Eventually, this may help to truly individualize the dosing of this (and other) anti-cancer agent(s), using a personal genetic profile of the most relevant enzymes for every patient.
AuthorsFloris A de Jong, Maja J A de Jonge, Jaap Verweij, Ron H J Mathijssen
JournalCancer letters (Cancer Lett) Vol. 234 Issue 1 Pg. 90-106 (Mar 08 2006) ISSN: 0304-3835 [Print] Ireland
PMID16343744 (Publication Type: Journal Article, Review)
Chemical References
  • ABCC2 protein, human
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents, Phytogenic
  • Multidrug Resistance-Associated Protein 2
  • Irinotecan
  • Camptothecin
Topics
  • ATP-Binding Cassette Transporters (genetics, metabolism)
  • Animals
  • Antineoplastic Agents, Phytogenic (therapeutic use)
  • Camptothecin (analogs & derivatives, therapeutic use)
  • Forecasting
  • Humans
  • Irinotecan
  • Multidrug Resistance-Associated Protein 2
  • Neoplasms (drug therapy, genetics)
  • Pharmacogenetics
  • Polymorphism, Genetic (genetics)

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