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Ribonucleotide reductase M1 (RRM1) 2464G>A polymorphism shows an association with gemcitabine chemosensitivity in cancer cell lines

Kwon, Woo Suna b; Rha, Sun Younga b c; Choi, Yeon Hoa b; Lee, Jung Oka; Park, Kyu Hyuna c; Jung, Jae Joona b; Kim, Tae Sooa c; Jeung, Hei-Cheula c; Chung, Hyun Cheola b c d

Pharmacogenetics and Genomics: June 2006 - Volume 16 - Issue 6 - p 429-438
doi: 10.1097/01.fpc.0000204999.29924.da
ORIGINAL ARTICLES
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Objectives Significant variability in the efficacy and toxicity of an anticancer drug is observed in cancer patients. Currently, there are no standard tools for prediction of a patient's tumor response or his risk of adverse events to chemotherapy.

Methods We investigate an association between polymorphisms of gemcitabine metabolism-related genes and its chemosensitivity in vitro using 62 human cancer cell lines of various origins. Polymorphisms of gemcitabine metabolism-related genes of deoxycytidine monophosphate deaminase (DCTD), deoxycytidine kinase (DCK) and ribonucleotide reductase M1 (RRM1) were evaluated using the CEQ8000 Genetic analysis system and GeneDoc software. Chemosensitivity of gemcitabine was expressed as an IC50 using MTT assay.

Results The frequency of the polymorphisms was 21% in DCTD 315T>C, 45.2% in RRM1 1082C>A, 59.7% in RRM1 2455A>G, and 79% in RRM1 2464G>A. When examining the association between these polymorphisms and IC50, only the RRM1 2464G>A showed the tendency to be more chemosensitive to gemcitabine (P=0.011), and haplotypes containing 2464G>A polymorphism also showed the association with chemosensitivity when compared to wild-type RRM1 (G2464G). We could not see the significant differences of mRNA expression level with real-time PCR between cell lines according to G2464A polymorphism. In oligonucleotide microarray 73 GenBank Accession Number (69 genes) were selected which expressed differently between RRM1 wild-type and the G2464A polymorphism.

Conclusions RRM1 2464G>A polymorphism demonstrated an association with gemcitabine sensitivity, which needs functional studies with co-expressing genes and prospective clinical studies for the clinical application as a predictive bio-marker.

aCancer Metastasis Research Center

bBrain Korea 21 Project for Medical Science

cYonsei Cancer Center, Yonsei Cancer Research Institute

dDepartment of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea

Correspondence and requests for reprints to Hyun Cheol Chung, Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University College of Medicine, 134 Shinchon-Dong, Seodaemun-Gu, Seoul, Korea, 120–752

Tel: +82 (2) 2228-8132; fax: +82 (2) 393–3652;

e-mail: unchung8@yumc.yonsei.ac.kr

This work was supported in part by the Korea Science and Engineering Foundation (KOSEF) through the Cancer Metastasis Research Center (CMRC) at Yonsei University College of Medicine. This study was supported in part by grant 03-PJ10-PG13-GD01–0002 from the Korea Health 21 R & D Project, Ministry of Health & Welfare, Korea.

Received 4 December 2005 Accepted 7 January 2006

© 2006 Lippincott Williams & Wilkins, Inc.