Thymidylate synthase and thymidine phosphorylase gene expression as predictive parameters for the efficacy of 5-fluorouraci-based adjuvant chemotherapy for gastric cancer

AIM: To investigate the prognostic role of thymidylate synthase (TS) and thymidine phosphorylase (TP) mRNA levels in T3 or T4 gastric cancer treated with 5-fluorouraci-based adjuvant chemotherapy. METHODS: Fifty-one patients with T3 or T4 gastric cancer received systemic 5-fluorouraci-based adjuvant chemotherapy, and intratumoral expression of TS and TP in 51 gastric cancer tissue samples was tested by real-time quantitative PCR. RESULTS: The median disease-free survival (DFS) time was 10.2 mo in the patients. There were no significant differences in DFS between the groups with high and low levels of TP. However, the group with low level of TS had a longer DFS (14.4 mo vs 8.3 mo, P = 0.017). The median overall survival (OS) time was 18.5 mo, and there were significant differences in OS between the groups with high and low levels of TS or TP (for TS, 17.0 mo vs 21.3 mo, P = 0.010; for TP, 16.6 mo vs 22.5 mo, P = 0.009). Moreover, the coupled low expression of these two genes was strongly associated with a longer survival time of patients as compared with that of a single gene. CONCLUSION: Expression of TS and TP mRNA is a useful predictive parameter for the survival of postoperative gastric cancer patients after 5-fluorouracil-based adjuvant chemotherapy.

[1]  Y. Kodera,et al.  Gene expression of 5-fluorouracil metabolic enzymes in primary gastric cancer: correlation with drug sensitivity against 5-fluorouracil. , 2007, Cancer letters.

[2]  J. Meyerhardt,et al.  Adjuvant and Neoadjuvant Approaches in Gastric Cancer , 2007, Cancer journal.

[3]  T. Ijuin,et al.  Thymidine phosphorylase mRNA level predicts survival of patients with advanced oropharyngeal cancer , 2007, Acta oto-laryngologica.

[4]  G. Fontanini,et al.  Thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase expression in colorectal cancer and normal mucosa in patients , 2006, Pharmacogenetics and genomics.

[5]  J. Ajani.  Evolving chemotherapy for advanced gastric cancer. , 2005, The oncologist.

[6]  Wooin Lee,et al.  Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development. , 2005, The oncologist.

[7]  T. Kubota,et al.  Thymidylate synthetase (TS) genotype and TS/dihydropyrimidine dehydrogenase mRNA level as an indicator in determining chemosensitivity to 5-fluorouracil in advanced gastric carcinoma. , 2004, Anticancer research.

[8]  Yan-zhen Lin,et al.  Correlation of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase with sensitivity of gastrointestinal cancer cells to 5-fluorouracil and 5-fluoro-2'-deoxyuridine. , 2004, World journal of gastroenterology.

[9]  M. Ikeguchi,et al.  Thymidine phosphorylase and dihydropyrimidine dehydrogenase activity in colorectal carcinoma and patients prognosis , 2002, Langenbeck's Archives of Surgery.

[10]  G. Watanabe,et al.  Association of thymidylate synthase gene polymorphism with its mRNA and protein expression and with prognosis in gastric cancer. , 2002, Anticancer research.

[11]  A. Dubreuil,et al.  Impact of thymidine phosphorylase surexpression on fluoropyrimidine activity and on tumour angiogenesis , 2001, British Journal of Cancer.

[12]  A. Monks,et al.  Thymidine kinase, thymidylate synthase, and dihydropyrimidine dehydrogenase profiles of cell lines of the National Cancer Institute's Anticancer Drug Screen. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[13]  Martin R. Johnson,et al.  The Role of Pharmacogenetics and Pharmacogenomics in Cancer Chemotherapy with 5-Fluorouracil , 2000, Pharmacology.

[14]  N. Nagasue,et al.  Expression levels of thymidine phosphorylase and dihydropyrimidine dehydrogenase in various human tumor tissues. , 2000, International journal of oncology.

[15]  S. Tsujitani,et al.  The expression of thymidine phosphorylase correlates with angiogenesis and the efficacy of chemotherapy using fluorouracil derivatives in advanced gastric carcinoma , 1999, British Journal of Cancer.

[16]  S. Akiba,et al.  Clinicopathologic and prognostic significance of an angiogenic factor, thymidine phosphorylase, in human colorectal carcinoma. , 1996, Journal of the National Cancer Institute.

[17]  W. Ichikawa.  Prediction of clinical outcome of fluoropyrimidine-based chemotherapy for gastric cancer patients, in terms of the 5-fluorouracil metabolic pathway , 2006, Gastric Cancer.

[18]  W. Evans,et al.  Pharmacogenomics: unlocking the human genome for better drug therapy. , 2001, Annual review of pharmacology and toxicology.

[19]  S. Groshen,et al.  ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  S. Groshen,et al.  Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.