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

Lookup NU author(s): Dr Simon Pridgeon, Professor Rakesh Heer, Gordon Taylor, Emeritus Professor Herbie Newell, Kieran O'Toole, Professor Alan Boddy

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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 mM) replaced up to 0.63% of thymidine in rat and tumour bladder cancer cells. The combination of S4TdR (10-200 mu M) and UVA (1-5 kJm(-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 IC5) 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. British Journal of Cancer (2011) 104, 1869-1876. doi:10.1038/bjc.2011.180 www.bjcancer.com Published online 24 May 2011 (C) 2011 Cancer Research UK


Publication metadata

Author(s): Pridgeon SW, Heer R, Taylor GA, Newell DR, O'Toole K, Robinson M, Xu YZ, Karran P, Boddy AV

Publication type: Article

Publication status: Published

Journal: British Journal of Cancer

Year: 2011

Volume: 104

Issue: 12

Pages: 1869-1876

Print publication date: 24/05/2011

ISSN (print): 0007-0920

ISSN (electronic): 1532-1827

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/bjc.2011.180

DOI: 10.1038/bjc.2011.180


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