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Research Articles: Therapeutics, Targets, and Development

Thiothymidine plus low-dose UVA kills hyperproliferative human skin cells independently of their human papilloma virus status

¹ Cancer Research UK, Institute for Cell and Molecular Science, Skin Tumour Laboratory, London, United Kingdom; ² Department of Chemistry, The Open University, Milton Keynes, United Kingdom; and ³ Cancer Research UK, London Research Institute, Clare Hall Laboratories, Herts, United Kingdom

Requests for reprints: Alan Storey, Cancer Research UK, Institute for Cell and Molecular Science, Skin Tumour Laboratory, 4, Newark Street, London E1 2AT, United Kingdom. Phone: 44-207-882-7164; Fax: 44-207-882-7171. E-mail: alan.storey{at}cancer.org.uk

Abstract

The thymidine analogue 4-thiothymidine (S⁴TdR) is a photosensitizer for UVA radiation. The UV absorbance spectrum of S⁴TdR and its incorporation into DNA suggests that it might act synergistically with nonlethal doses of UVA to selectively kill hyperproliferative or cancerous skin cells. We show here that nontoxic concentrations of S⁴TdR combine with nonlethal doses of UVA to kill proliferating cultured skin cells. Established cell lines with a high fraction of proliferating cells were more sensitive than primary keratinocytes or fibroblasts to apoptosis induction by S⁴TdR/UVA. Although S⁴TdR plus UVA treatment induces stabilization of p53, cell death, as measured by apoptosis or clonal survival, occurs to a similar extent in both p53 wild-type and p53-null backgrounds. Furthermore, different types of human papilloma virus E6 proteins, which protect against UVB-induced apoptosis, have little effect on killing by S⁴TdR/UVA. S⁴TdR/UVA offers a possible therapeutic intervention strategy that seems to be applicable to human papilloma virus–associated skin lesions. [Mol Cancer Ther 2007;6(9):2487–95]

Grant support: Translational fellowship (no. TR4020) from Cancer Research UK (O. Reelfs, A. Storey, and P. Karran).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Present address for A. Massey: Vernalis Ltd., Granta Park, Cambridge CB1 6GB, United Kingdom.

⁴ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

⁵ Reelfs O, Montaner B. unpublished data.

Received 3/ 8/07; revised 6/ 4/07; accepted 8/ 1/07.