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PURPOSE: It has been previously demonstrated that the angiogenic factor thymidine phosphorylase is elevated significantly in invasive bladder cancer. We report that it is not merely an incidental finding. Thymidine phosphorylase has a functional role in bladder cancer invasion. MATERIALS AND METHODS: The superficial bladder cancer cell line RT112 was transfected by retroviral techniques to generate the RT112-TP clone that expressed significantly elevated levels of thymidine phosphorylase, comparable to those of invasive human bladder cancers. The empty vector control RT112-EV was generated for comparison. Growth of these transfectants was examined using a new in vitro model of bladder cancer invasion based on de-epithelialized rat bladder and by assessing growth as xenografts in nude mice. The effect of 5-deoxy-5-fluorouridine, a prodrug activated by TP to produce 5-fluorouracil, was also examined. RESULTS: RT112-TP high thymidine phosphorylase expressing cells invaded into the stroma of the in vitro model but wild-type RT112 and RT112-EV cells did not. This invasion was abolished by 5-deoxy-5-fluorouridine. Invasion correlated with thymidine phosphorylase expression on immunohistochemical testing. There was also a significantly greater xenograft growth rate for RT112-TP than for RT112-EV, confirming the malignant growth advantage conferred by thymidine phosphorylase. CONCLUSIONS: We demonstrated that thymidine phosphorylase may have a functional role in bladder cancer invasion and the apparent advantage of thymidine phosphorylase expression to tumor cells can be exploited by therapies that utilize prodrugs such as 5-deoxy-5-fluorouridine, which is activated by thymidine phosphorylase and inhibited invasion in our model.

Type

Journal article

Journal

J Urol

Publication Date

03/2002

Volume

167

Pages

1482 - 1486

Keywords

Animals, Carcinoma, Transitional Cell, Disease Models, Animal, Humans, In Vitro Techniques, Mice, Mice, Nude, Neoplasm Invasiveness, Prodrugs, Rats, Thymidine Phosphorylase, Transfection, Tumor Cells, Cultured, Urinary Bladder Neoplasms