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Genetic linkage of UGT1A7 and UGT1A9 polymorphisms to UGT1A1*6 is associated with reduced activity for SN-38 in Japanese patients with cancer

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Abstract

Purpose

The phenotypic effects of UGT1A7 and UGT1A9 genetic polymorphisms on the in vivo pharmacokinetics of irinotecan were examined.

Methods

Eighty-four Japanese patients with cancer who received irinotecan-based chemotherapy were enrolled. Polymorphisms present in UGT1A7 (T to G transversion at −57 and UGT1A7*2 to *9), UGT1A9 (9 or 10 repeat of T at −118 [−118(T)9 or 10] and UGT1A9*2 to *5), and UGT1A1 (UGT1A1*6, UGT1A1*27, and UGT1A1*28) were analyzed for all patients. Pharmacokinetics of irinotecan were examined in 52 patients.

Results

The most frequent haplotype (haplotype I, 56.7%, 95% CI 53.1–60.4) consisted of polymorphisms related to normal catalytic or transcriptional activity [T at −57 and *1 of UGT1A7, −118(T)10 of UGT1A9, and UGT1A1*1]. The second most frequent haplotype (haplotype II, 15.0%, 95% CI 12.4–18.3) consisted of polymorphisms related to reduced catalytic or transcriptional activity [−57T > G and *3 of UGT1A7 and −118(T)9 of UGT1A9 linked to UGT1A1*6]. The AUCSN-38/AUCSN-38G ratios in three patients homozygous for haplotype II were significantly higher than those in 20 patients with I/I diplotype (P = 0.011). Neither of these patients had UGT1A1*28.

Conclusion

Genetic linkage of UGT1A7 and UGT1A9 polymorphisms to UGT1A1*6, related to reduced catalytic and transcriptional activities of UGTs, is associated with the decreased glucuronosyltransferase activity for SN-38 in Japanese patients with cancer.

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Acknowledgments

We thank Ms. Yuko Akiyama for technical help in the genotype analysis as well as Ms. Kaori Kawara for serving as a research nurse. This study was supported in part by a Grant-in-Aid from the Ministry of Health and Welfare of Japan (13-10). This study was presented in part at the 97th Annual Meeting of American Association for Cancer Research, Washington, DC, April 1–5, 2006.

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Authors and Affiliations

  1. Department of Clinical Oncology, Saitama Medical University, 38 Morohongou, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan

    Ken-ichi Fujita, Yuichi Ando, Fumio Nagashima, Wataru Yamamoto, Hisashi Eodo, Kazuhiro Araki, Keiji Kodama, Toshimichi Miya, Masaru Narabayashi & Yasutsuna Sasaki

  2. Project Research Laboratory, Research Center for Genomic Medicine, Saitama Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1241, Japan

    Ken-ichi Fujita

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  1. Ken-ichi Fujita
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Correspondence to Yasutsuna Sasaki.

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Fujita, Ki., Ando, Y., Nagashima, F. et al. Genetic linkage of UGT1A7 and UGT1A9 polymorphisms to UGT1A1*6 is associated with reduced activity for SN-38 in Japanese patients with cancer. Cancer Chemother Pharmacol 60, 515–522 (2007). https://doi.org/10.1007/s00280-006-0396-1

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