title: DNA repair inhibition by UVA photoactivated fluoroquinolones and vemurafenib.
abstract: Cutaneous photosensitization is a common side effect of drug treatment and can be associated with an increased skin cancer risk. The immunosuppressant azathioprine, the fluoroquinolone antibiotics and vemurafenib-a BRAF inhibitor used to treat metastatic melanoma-are all recognized clinical photosensitizers. We have compared the effects of UVA radiation on cultured human cells treated with 6-thioguanine (6-TG, a DNA-embedded azathioprine surrogate), the fluoroquinolones ciprofloxacin and ofloxacin and vemurafenib. Despite widely different structures and modes of action, each of these drugs potentiated UVA cytotoxicity. UVA photoactivation of 6-TG, ciprofloxacin and ofloxacin was associated with the generation of singlet oxygen that caused extensive protein oxidation. In particular, these treatments were associated with damage to DNA repair proteins that reduced the efficiency of nucleotide excision repair. Although vemurafenib was also highly phototoxic to cultured cells, its effects were less dependent on singlet oxygen. Highly toxic combinations of vemurafenib and UVA caused little protein carbonylation but were nevertheless inhibitory to nucleotide excision repair. Thus, for three different classes of drugs, photosensitization by at least two distinct mechanisms is associated with reduced protection against potentially mutagenic and carcinogenic DNA damage.
authors.affiliation: Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts. EN6 3LD, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Peacock
authors.affiliation: Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts. EN6 3LD, UK.
authors.forename: Reto
authors.initials: R
authors.lastname: Brem
authors.affiliation: Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts. EN6 3LD, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Macpherson
authors.affiliation: Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts. EN6 3LD, UK peter.karran@cancer.org.uk.
authors.forename: Peter
authors.initials: P
authors.lastname: Karran
mesh_terms: D000900:Anti-Bacterial Agents / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity*; D002460:Cell Line; D002939:Ciprofloxacin / Q000633:toxicity; D004260:DNA Repair / Q000187:drug effects* / Q000528:radiation effects; D024841:Fluoroquinolones / Q000633:toxicity*; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000633:toxicity*; D015242:Ofloxacin / Q000633:toxicity; D017319:Photosensitizing Agents / Q000633:toxicity*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D050050:Protein Carbonylation / Q000187:drug effects* / Q000528:radiation effects; D013449:Sulfonamides / Q000633:toxicity*; D013866:Thioguanine / Q000633:toxicity; D014466:Ultraviolet Rays / Q000009:adverse effects*; D000077484:Vemurafenib
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D024841:Fluoroquinolones; D007211:Indoles; D017319:Photosensitizing Agents; D018809:Proliferating Cell Nuclear Antigen; D013449:Sulfonamides; D000077484:Vemurafenib; D002939:Ciprofloxacin; D015242:Ofloxacin; D013866:Thioguanine