Impact of UDP-Glucuronosyltransferase 1A Haplotypes on Irinotecan Treatment

  • Kimie Sai
  • Hironobu Minami
  • Yoshiro Saito
  • Jun-ichi Sawada
Part of the Cancer Drug Discovery and Development™ book series (CDD&D)


Irinotecan, an antineoplastic-prodrug, is widely used for the treatment of colorectal, lung and other cancers, and is one of model pharmaceuticals for personalized medicine. The active metabolite, SN-38, is a topoisomerase I inhibitor generated by hydrolysis of irinotecan by carboxylesterases. SN-38 is subsequently glucuronidated by uridine diphosphate glucuronosyltransferase 1As (UGT1As) to form an inactive metabolite, SN-38 G. A reduction in SN-38 G formation is closely related to severe irinotecan toxicities (diarrhea and neutropenia). Therefore, the association of UGT1A1 polymorphisms with irinotecan toxicities has been intensively studied. A number of recent irinotecan-pharmacogenetic studies have revealed significant associations between UGT1A1*28 and severe irinotecan toxicities, leading to the introduction of the clinical application of *28 genetic testing in the United States. This paper provides an overview of recent progress in irinotecan pharmacogenetics, focusing on updated findings on the haplotype structures of UGT1As and addressing the clinical significance of UGT1A1 genotypes/haplotypes to severe irinotecan toxicities. Issues that must be addressed for improvement of personalized irinotecan therapy are also discussed.

Key Words

UGT1A1 UGT1A7 UGT1A9 pharmacogenetics irinotecan SN-38 Haplotype 


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Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Kimie Sai
    • 1
  • Hironobu Minami
  • Yoshiro Saito
  • Jun-ichi Sawada
  1. 1.Division of BiosignalingNational Institute of Health SciencesTokyoJapan

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