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 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.
Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts. EN6 3LD, UK. Electronic address: reto.brem@cancer.org.uk.
Reto
R
Brem
College of Environment and Chemical Engineering, Dalian University, Dalian 116622, China.
Xiaohui
X
Zhang
Department of Life, Health and Chemical Sciences, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK.
Yao-Zhong
YZ
Xu
Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts. EN6 3LD, UK.
Peter
P
Karran
D000818:Animals; D002460:Cell Line; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004249:DNA Damage / Q000528:radiation effects; D045647:DNA Glycosylases / Q000737:chemistry / Q000378:metabolism; D054879:Halogenation; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D010084:Oxidation-Reduction; D011740:Pyrimidine Dimers / Q000737:chemistry; D026082:Singlet Oxygen / Q000737:chemistry / Q000378:metabolism; D013891:Thiouridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D014466:Ultraviolet Rays
C000603453:5-bromo-4-thiodeoxyuridine; C000603454:5-iodo-4-thiodeoxyuridine; D011740:Pyrimidine Dimers; C058406:pyrimidine-pyrimidone dimer; D013891:Thiouridine; D026082:Singlet Oxygen; D004247:DNA; D045647:DNA Glycosylases