Adrian L. Harris

ROLE OF THYMIDINE PHOSPHORYLASE IN AN IN VITRO MODEL OF HUMAN BLADDER CANCER INVASION

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.

Abstract LB-450: Necrosis predicts benefit from hypoxia-modifying therapy in urothelial cell carcinoma of the bladder

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL To investigate the ability of tumor necrosis to predict benefit following radiotherapy with and without hypoxia-modifying treatment in high grade urothelial cell carcinoma of the urinary bladder. Background: There is no predictive marker of hypoxia-modifying therapy in cancer patients in routine clinical use. Methods: We identified 231 patients who participated in the BCON phase III randomised trial comparing radical radiotherapy (RT) with and without carbogen and nicotinamide (CON) in patients with urothelial cell carcinoma of the bladder who were suitable for this retrospective study. Tumor necrosis was scored on whole tissue sections as absent or present. Results: Tumor necrosis was identified in 121 of the 231 patients (52%). 5-year overall survival estimates were 41% for the RT arm and 48% for the CON arm (log rank p=0.14). When stratified using tumor necrosis, the 5-year overall survival estimates were 48% (RT) and 39% (CON) (log rank p =0.32) in patients with no evident tumor necrosis, and 34% (RT) and 56% (CON) (log rank p=0.004) in patients with tumor necrosis. Multivariate analyses showed that the presence of tumor necrosis was a significant predictor of benefit from CON with the risk of dying 57% lower compared to RT alone (HR 0.43, 95% CI 0.25-0.73, p=0.002). This trend was not observed when there is no evident tumour necrosis (HR 1.64, 95% CI 0.95-2.85, p=0.08). Test for heterogeneity in treatment effect by necrosis strata (p=0.007 unadjusted, p=0.001 adjusted). Conclusions: Tumor necrosis significantly predicts benefit from radiotherapy with hypoxia-modifying treatment. Independent validation in a prospective trial is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-450. doi:1538-7445.AM2012-LB-450