Role of thymidine phosphorylase in an in vitro model of human bladder cancer invasion.
OBJECTIVE
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.


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.
Jones
Adam
A
Imperial Cancer Research Fund, University of Oxford Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
Fujiyama
Chisato
C
Turner
Kevin
K
Cranston
David
D
Williams
Kaye
K
Stratford
Ian
I
Bicknell
Roy
R
Harris
Adrian L
AL
D000818:Animals; D002295:Carcinoma, Transitional Cell; D004195:Disease Models, Animal; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D011355:Prodrugs; D051381:Rats; D013939:Thymidine Phosphorylase / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000473:pathology*
D011355:Prodrugs; D013939:Thymidine Phosphorylase