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Pharmacogenetics of irinotecan

G Toffoli1, E Cecchin, G Corona

  • 1Experimental and Clinical Pharmacology, Unit CRO-National Cancer Institute, 33081 Aviano-PN, Italy. gtoffoli@cro.it

Current Medicinal Chemistry. Anti-Cancer Agents
|May 29, 2003
PubMed

Insights

Pharmacogenetics examines genetic variations affecting drug response. Understanding genetic polymorphisms in irinotecan metabolism is crucial for predicting anticancer drug toxicity and personalizing patient treatment.

Area of Science:

  • Pharmacogenetics and Oncology
  • Drug Metabolism and Pharmacokinetics

Background:

  • Anticancer drugs, like irinotecan, often have a narrow safety margin, leading to unpredictable severe toxicity.
  • Irinotecan's complex metabolism involves multiple proteins, including human carboxylesterase (hCE1, hCE2), cytochrome P450 (CYP3A4, CYP3A5), uridino-glucuronosil transferase (UGT1A1), multi-resistance protein 2 (MRP2), and P-glycoprotein (MDR1).
  • Genetic polymorphisms in these metabolizing enzymes can significantly influence irinotecan's efficacy and toxicity, with UGT1A1*28 allele linked to increased toxicity.

Purpose of the Study:

  • To review recent advancements in the pharmacogenetics of irinotecan.
  • To highlight the importance of individual genetic profiles in predicting irinotecan's toxicity and therapeutic effectiveness.
  • To emphasize the need for personalized irinotecan therapy based on pharmacogenetic data.

Main Methods:

  • Review of scientific literature on irinotecan pharmacogenetics.
  • Analysis of genetic polymorphisms in key drug-metabolizing enzymes.
  • Correlation of genetic variations with clinical outcomes and toxicity profiles.

Main Results:

  • Multiple genes involved in irinotecan metabolism exhibit polymorphic variations.
  • The UGT1A1*28 allele is specifically associated with heightened irinotecan-induced toxicity.
  • Traditional clinical parameters like body-surface area show limited correlation with irinotecan treatment outcomes.

Conclusions:

  • Individual genetic makeup significantly impacts irinotecan's efficacy and toxicity.
  • Pharmacogenetic profiling is essential for predicting patient response to irinotecan.
  • Personalized medicine approaches, guided by pharmacogenetics, are crucial for optimizing irinotecan chemotherapy.

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