Thiothymidine combined with UVA as a potential novel therapy for bladder cancer

Abstract

Background:Thiothymidine (S 4 TdR) can be incorporated into DNA and sensitise cells to DNA damage and cell death following exposure to UVA light. Studies were performed to determine if the combination of S 4 TdR and UVA could be an effective treatment for bladder cancer.Methods:Uptake and incorporation of S 4 TdR was determined in rat and human bladder tumour cell lines. Measures of DNA crosslinking and apoptosis were also performed. In vivo activity of the combination of S 4 TdR and UVA was investigated in an orthotopic model of bladder cancer in rats.Results:Thiothymidine (200 M) replaced up to 0.63% of thymidine in rat and tumour bladder cancer cells. The combination of S 4 TdR (10-200 M) and UVA (1-5 kJ m 2) caused apoptosis and cell death at doses that were not toxic alone. Addition of raltitrexed (Astra Zeneca, Alderley Edge, Cheshire, UK) increased the incorporation of S 4 TdR into DNA (up to 20-fold at IC 5) and further sensitised cells to UVA. Cytotoxic effect was associated with crosslinking of DNA, at least partially to protein. Intravenous administration of S 4 TdR, in combination with UVA delivered directly to the bladder, resulted in an antitumour effect in three of five animals treated.Conclusion:These data indicate that the combination of S 4 TdR and UVA has potential as a treatment for bladder cancer, and give some insight into the mechanism of action. Further work is necessary to optimise the delivery of the two components. © 2011 Cancer Research UK All rights reserved.