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Photoactivation of DNA thiobases as a potential novel therapeutic option

Massey, Andrew; Xu, Yao-Zhong and Karran, Peter (2001). Photoactivation of DNA thiobases as a potential novel therapeutic option. Current Biology, 11(14) pp. 1142–1146.

DOI (Digital Object Identifier) Link: http://dx.doi.org/10.1016/S0960-9822(01)00272-X
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Abstract

The thiopurines, 6-thioguanine and 6-mercaptopurine, are antileukemic agents that are incorporated into DNA following retrieval by the purine salvage pathway (see [1] for a review). Their toxicity requires active DNA mismatch repair (MMR), and thiopurine resistance is an acknowledged phenotype of MMR-defective cells [2, 3]. In addition to these direct cytotoxic effects, DNA thiobases have distinctive photochemical properties [4], the therapeutic potential of which has not been extensively evaluated. We report here that the thiopyrimidine nucleoside 4-thiothymidine is incorporated into DNA. It does not induce MMR-related toxicity, but it interacts synergistically with UVA light and dramatically sensitizes cultured human cells to very low, nonlethal UVA doses. 4-thiothymidine induced UVA dose enhancements of around 100-fold in DNA repair-proficient cells. Nucleotide excision repair-defective xeroderma pigmentosum cells were sensitized up to 1000-fold, implicating bulky DNA photoproducts in the lethal effect. The synergistic action of thiothymidine plus UVA required thymidine kinase, indicating a selective toxicity toward rapidly proliferating cells. Cooperative UVA cytotoxicity is a general property of DNA thiobases, and 6-thioguanine and 4-thiodeoxyuridine were also UVA sensitizers. Thiobase/UVA treatment may offer a novel therapeutic approach for the clinical management of nonmalignant conditions like psoriasis or for superficial tumors that are accessible to phototherapy.

Item Type: Journal Article
ISSN: 0960-9822
Extra Information: Some of the symbols may not have transferred correctly into this bibliographic record and/or abstract.
Academic Unit/Department: Science > Life, Health and Chemical Sciences
Interdisciplinary Research Centre: Biomedical Research Network (BRN)
Item ID: 3849
Depositing User: Yao Xu
Date Deposited: 14 Aug 2006
Last Modified: 10 Mar 2014 09:32
URI: http://oro.open.ac.uk/id/eprint/3849
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