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

Pridgeon, S. W.; Heer, R.; Taylor, G. A.; Newell, D. R.; O'Toole, K.; Robinson, M.; Xu, Y-Z; Karran, P. and Boddy, A. V. (2011). Thiothymidine combined with UVA as a potential novel therapy for bladder cancer. British Journal of Cancer, 104(12) pp. 1869–1876.

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DOI (Digital Object Identifier) Link: http://dx.doi.org/10.1038/bjc.2011.180
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Abstract

BACKGROUND: Thiothymidine (S4TdR) 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 S4TdR and UVA could be an effective treatmentfor bladder cancer.

METHODS: Uptake and incorporation of S4TdR 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 S4TdR and UVA was investigated in an orthotopic model of bladder cancer in rats.

RESULTS: Thiothymidine (200 uM) replaced up to 0.63% of thymidine in rat and tumour bladder cancer cells. The combination of S4TdR (10–200 uM) 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 S4TdR 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 S4TdR, 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 S4TdR 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.

Item Type: Journal Article
Copyright Holders: 2011 Cancer Research UK
ISSN: 0007-0920
Keywords: Thiothymidine; UVA; bladder cancer; raltitrexed; DNA damage
Academic Unit/Department: Science > Life, Health and Chemical Sciences
Interdisciplinary Research Centre: Biomedical Research Network (BRN)
Item ID: 29061
Depositing User: Yao Xu
Date Deposited: 14 Jul 2011 09:10
Last Modified: 14 Mar 2014 14:12
URI: http://oro.open.ac.uk/id/eprint/29061
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