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UVA photoactivation of DNA containing halogenated thiopyrimidines induces cytotoxic DNA lesions

Photochemotherapy, the combination of a photosensitiser and ultraviolet (UV) or visible light, is an effective treatment for skin conditions including cancer. The high mutagenicity and non-selectivity of photochemotherapy regimes warrants the development of alternative approaches. We demonstrate tha...

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Autores principales: Brem, Reto, Zhang, Xiaohui, Xu, Yao-Zhong, Karran, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Sequoia 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376468/
https://www.ncbi.nlm.nih.gov/pubmed/25747491
http://dx.doi.org/10.1016/j.jphotobiol.2015.02.012
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author Brem, Reto
Zhang, Xiaohui
Xu, Yao-Zhong
Karran, Peter
author_facet Brem, Reto
Zhang, Xiaohui
Xu, Yao-Zhong
Karran, Peter
author_sort Brem, Reto
collection PubMed
description Photochemotherapy, the combination of a photosensitiser and ultraviolet (UV) or visible light, is an effective treatment for skin conditions including cancer. The high mutagenicity and non-selectivity of photochemotherapy regimes warrants the development of alternative approaches. We demonstrate that the thiopyrimidine nucleosides 5-bromo-4-thiodeoxyuridine (SBrdU) and 5-iodo-4-thiodeoxyuridine (SIdU) are incorporated into the DNA of cultured human and mouse cells where they synergistically sensitise killing by low doses of UVA radiation. The DNA halothiopyrimidine/UVA combinations induce DNA interstrand crosslinks, DNA-protein crosslinks, DNA strand breaks, nucleobase damage and lesions that resemble UV-induced pyrimidine(6-4)pyrimidone photoproducts. These are potentially lethal DNA lesions and cells defective in their repair are hypersensitive to killing by SBrdU/UVA and SIdU/UVA. DNA SIdU and SBrdU generate lethal DNA photodamage by partially distinct mechanisms that reflect the different photolabilities of their C–I and C–Br bonds. Although singlet oxygen is involved in photolesion formation, DNA SBrdU and SIdU photoactivation does not detectably increase DNA 8-oxoguanine levels. The absence of significant collateral damage to normal guanine suggests that UVA activation of DNA SIdU or SBrdU might offer a strategy to target hyperproliferative skin conditions that avoids the extensive formation of a known mutagenic DNA lesion.
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spelling pubmed-43764682015-04-01 UVA photoactivation of DNA containing halogenated thiopyrimidines induces cytotoxic DNA lesions Brem, Reto Zhang, Xiaohui Xu, Yao-Zhong Karran, Peter J Photochem Photobiol B Article Photochemotherapy, the combination of a photosensitiser and ultraviolet (UV) or visible light, is an effective treatment for skin conditions including cancer. The high mutagenicity and non-selectivity of photochemotherapy regimes warrants the development of alternative approaches. We demonstrate that the thiopyrimidine nucleosides 5-bromo-4-thiodeoxyuridine (SBrdU) and 5-iodo-4-thiodeoxyuridine (SIdU) are incorporated into the DNA of cultured human and mouse cells where they synergistically sensitise killing by low doses of UVA radiation. The DNA halothiopyrimidine/UVA combinations induce DNA interstrand crosslinks, DNA-protein crosslinks, DNA strand breaks, nucleobase damage and lesions that resemble UV-induced pyrimidine(6-4)pyrimidone photoproducts. These are potentially lethal DNA lesions and cells defective in their repair are hypersensitive to killing by SBrdU/UVA and SIdU/UVA. DNA SIdU and SBrdU generate lethal DNA photodamage by partially distinct mechanisms that reflect the different photolabilities of their C–I and C–Br bonds. Although singlet oxygen is involved in photolesion formation, DNA SBrdU and SIdU photoactivation does not detectably increase DNA 8-oxoguanine levels. The absence of significant collateral damage to normal guanine suggests that UVA activation of DNA SIdU or SBrdU might offer a strategy to target hyperproliferative skin conditions that avoids the extensive formation of a known mutagenic DNA lesion. Elsevier Sequoia 2015-04 /pmc/articles/PMC4376468/ /pubmed/25747491 http://dx.doi.org/10.1016/j.jphotobiol.2015.02.012 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Brem, Reto
Zhang, Xiaohui
Xu, Yao-Zhong
Karran, Peter
UVA photoactivation of DNA containing halogenated thiopyrimidines induces cytotoxic DNA lesions
title UVA photoactivation of DNA containing halogenated thiopyrimidines induces cytotoxic DNA lesions
title_full UVA photoactivation of DNA containing halogenated thiopyrimidines induces cytotoxic DNA lesions
title_fullStr UVA photoactivation of DNA containing halogenated thiopyrimidines induces cytotoxic DNA lesions
title_full_unstemmed UVA photoactivation of DNA containing halogenated thiopyrimidines induces cytotoxic DNA lesions
title_short UVA photoactivation of DNA containing halogenated thiopyrimidines induces cytotoxic DNA lesions
title_sort uva photoactivation of dna containing halogenated thiopyrimidines induces cytotoxic dna lesions
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376468/
https://www.ncbi.nlm.nih.gov/pubmed/25747491
http://dx.doi.org/10.1016/j.jphotobiol.2015.02.012
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