This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ichikawa, W. Articles by Hirayama, R. Search for Related Content PubMed PubMed Citation Articles by Ichikawa, W. Articles by Hirayama, R.

Orotate Phosphoribosyltransferase Gene Polymorphism Predicts Toxicity in Patients Treated with Bolus 5-Fluorouracil Regimen

Authors' Affiliations: Departments of ¹ General and Digestive Surgery and ² Clinical Oncology, Saitama Medical School, Iruma, Saitama, Japan

Requests for reprints: Wataru Ichikawa, Department of General and Digestive Surgery, Saitama Medical School, 38, Moro-Hongo, Moroyama, Iruma, Saitama 350-049, Japan. Phone: 81-49-276-1711; Fax: 81-49-276-1711; E-mail: wataru{at}saitama-med.ac.jp.

Purpose: We investigated whether the determination of orotate phosphoribosyltransferase (OPRT) and thymidylate synthase (TYMS) polymorphisms could predict the toxicity of 5-fluorouracil (5-FU) in colorectal cancer patients.

Experimental Design: The determination of OPRT and TYMS genotypes were done in genomic DNA extracted from blood by PCR amplification in 69 patients treated with bolus 5-FU as adjuvant chemotherapy. Associations between these polymorphisms and toxicity were evaluated retrospectively.

Results: The Ala allele in OPRT Gly²¹³Ala polymorphism and the two tandem repeats (2R) in TYMS promoter polymorphism were associated with grade 3 to 4 neutropenia and diarrhea. The multivariate logistic regression models revealed that only TYMS promoter polymorphism had an independent value to predict grade 3 to 4 neutropenia [odds ratio, 19.2 for patients with the 2R allele compared with patients with homozygous with the three repeat (3R) alleles], whereas both OPRT and TYMS promoter polymorphisms were independent predictive factors for grade 3 to 4 diarrhea (odds ratio, 13.3 for patients with the Ala allele compared with patients in the Gly/Gly genotype and 11.1 for patients with the 2R allele compared with patients in the 3R/3R genotype). A significant difference was observed in the time to onset of severe toxicity, defined as grade 4 neutropenia and/or grade 3 to 4 gastrointestinal toxicities according to OPRT and TYMS promoter polymorphisms.

Conclusion: OPRT Gly²¹³Ala polymorphism seems to be a useful marker for predicting toxicity to bolus 5-FU chemotherapy. Prospective translational treatment trials including larger number of patients are needed to confirm our results.

This article has been cited by other articles:

				E. Goekkurt, S.-E. Al-Batran, J. T. Hartmann, U. Mogck, G. Schuch, M. Kramer, E. Jaeger, C. Bokemeyer, G. Ehninger, and J. Stoehlmacher Pharmacogenetic Analyses of a Phase III Trial in Metastatic Gastroesophageal Adenocarcinoma With Fluorouracil and Leucovorin Plus Either Oxaliplatin or Cisplatin: A Study of the Arbeitsgemeinschaft Internistische Onkologie J. Clin. Oncol., June 10, 2009; 27(17): 2863 - 2873. [Abstract] [Full Text] [PDF]

				R. S. Huang and M. J. Ratain Pharmacogenetics and pharmacogenomics of anticancer agents CA Cancer J Clin, January 1, 2009; 59(1): 42 - 55. [Abstract] [Full Text] [PDF]

				A. Di Paolo, M. Lencioni, F. Amatori, S. Di Donato, G. Bocci, C. Orlandini, M. Lastella, F. Federici, M. Iannopollo, A. Falcone, et al. 5-Fluorouracil Pharmacokinetics Predicts Disease-free Survival in Patients Administered Adjuvant Chemotherapy for Colorectal Cancer Clin. Cancer Res., May 1, 2008; 14(9): 2749 - 2755. [Abstract] [Full Text] [PDF]