Peacock, MO; (2014) UVA Photosensitisers, Protein Oxidation and DNA Repair. Doctoral thesis , UCL (University College London).

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Abstract

Pharmaceuticals can interact with sunlight to cause skin photosensitization and increase skin cancer risk. Interaction of drug molecules with solar UVA or visible radiation results in electronically excited states that damage biomolecules directly or indirectly via the formation of reactive species (RS). RS cause damage to DNA and its precursors, as well as to proteins and lipids. I have devised methods to examine the induction of oxidative protein damage in cultured human cells and used these to investigate the effects of UVA-activated photosensitizing drugs on the formation of protein carbonyls and the oxidation of protein thiol groups. I examined the effects of 6-thioguanine (6-TG) (a surrogate for azathioprine, an immunosuppressant), fluoroquinolone antibiotics, and the malignant melanoma therapeutic vemurafenib, each of which is associated with clinical skin photosensitivity and increased skin cancer risk in patients. All of these drugs are shown to be synergistically cytotoxic with UVA in cultured human cells and toxicity is concurrent with the generation of RS. I identify singlet oxygen as a major component of these photochemically-generated RS and show that widespread protein oxidation is caused. The Ku DNA repair heterodimer is identified as one of several targets for oxidation damage and I show using biochemical assays that damage to Ku compromises its function in the repair of DNA strand breaks. UVA irradiation of cells treated with the photosensitisers significantly compromises the removal of potentially mutagenic DNA lesions by the nucleotide excision repair pathway. Since this DNA repair pathway removes sunlight-induced DNA lesions and is the major protection against skin cancer, my findings have implications for the increased skin cancer risk associated with azathioprine. The ability of structurally dissimilar drugs to recapitulate the effects of 6-TG suggests that the observations may share a common mechanism.

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