Tohoku J. Exp. Med., 2013 Feb, 229(2)

Polymorphisms of the UDP-Glucuronosyl Transferase 1A Genes Are Associated with Adverse Events in Cancer Patients Receiving Irinotecan-Based Chemotherapy

KAZUYUKI INOUE,¹ MOMOYO SONOBE,¹ YUKINORI KAWAMURA,¹ TAKASHI ETOH,² MASAKAZU TAKAGI,³ TAKASHI MATSUMURA,⁴ MASATAKA KIKUYAMA,⁴ MIDORI KIMURA,⁵ SATO MINAMI,⁵ HIROAKI UTSUKI,⁵ TOMOAKI YAMAZAKI,⁵ TAKAYO SUZUKI,⁵ DAIKI TSUJI,¹ HIDEKI HAYASHI¹ and KUNIHIKO ITOH¹

¹Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka City, Shizuoka, Japan
²Department of Respiratory Center, Shizuoka General Hospital, Shizuoka City, Shizuoka, Japan
³Department of Surgery, Shizuoka General Hospital, Shizuoka City, Shizuoka, Japan
⁴Department of Gastroenterology, Shizuoka General Hospital, Shizuoka City, Shizuoka, Japan
⁵Department of Pharmacy, Shizuoka General Hospital, Shizuoka City, Shizuoka, Japan

A prodrug, irinotecan (CPT-11), is a semisynthetic derivative of camptothecin. It inhibits topoisomerase I and is used for treatment of lung, stomach, and colon cancers in Japan. The active form of CPT-11, SN-38, causes the adverse events such as neutropenia and diarrhea. Since SN-38 is metabolized to non-toxic SN-38-glucuronide by hepatic uridine diphosphate glucuronosyl transferase (UGT) 1A enzymes, UGT1A enzyme activities may influence adverse events of CPT-11. UGT1A enzymes consist of three isozymes (1A1, 1A7, 1A9), and their genes are characterized by polymorphisms. Here, to identify the genetic factors that affect the adverse events of CPT-11, we determined the polymorphism in three UGT 1A isozyme genes in 45 inpatients with lung, colon, or stomach cancer. The univariate and multivariate analysis of patients' physiological and genetic factors revealed that one or more genotypes of UGT1A1*6/*28, UGT1A7*3/*3, and UGT1A9*1/*1 may enhance the adverse events. Each of the first two genotypes is expected to generate the enzyme with low catalytic activity. The UGT1A9*1 represents the wild-type allele, which however provides the lower catalytic activity, compared to the UGT1A9*22 variant that is common in this study population. Indeed, four (67%) out of six patients who carry one or more of the above-mentioned genotypes suffered from adverse events, leading to the discontinuation of chemotherapy or the decreased dose of CPT-11. By contrast, only six (15%) out of 39 patients with other genotypes suffered from adverse events. In conclusion, UGT1A1*6/*28, UGT1A7*3/*3, and UGT1A9*1/*1 should be taken into consideration as markers for preventing severe adverse events of CPT-11 administration.

keywords —— adverse event; genetic polymorphism; irinotecan; SN-38; UGT1A

© 2013 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2013, 229, 107-114

Correspondence: Kunihiko Itoh, Department of Clinical Pharmacology and Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526, Japan.

e-mail:itohk@u-shizuoka-ken.ac.jp