Photoactivation of DNA thiobases as a potential novel therapeutic option.
The thiopurines, 6-thioguanine and 6-mercaptopurine, are antileukemic agents that are incorporated into DNA following retrieval by the purine salvage pathway (see [1] for a review). Their toxicity requires active DNA mismatch repair (MMR), and thiopurine resistance is an acknowledged phenotype of MMR-defective cells [2, 3]. In addition to these direct cytotoxic effects, DNA thiobases have distinctive photochemical properties [4], the therapeutic potential of which has not been extensively evaluated. We report here that the thiopyrimidine nucleoside 4-thiothymidine is incorporated into DNA. It does not induce MMR-related toxicity, but it interacts synergistically with UVA light and dramatically sensitizes cultured human cells to very low, nonlethal UVA doses. 4-thiothymidine induced UVA dose enhancements of around 100-fold in DNA repair-proficient cells. Nucleotide excision repair-defective xeroderma pigmentosum cells were sensitized up to 1000-fold, implicating bulky DNA photoproducts in the lethal effect. The synergistic action of thiothymidine plus UVA required thymidine kinase, indicating a selective toxicity toward rapidly proliferating cells. Cooperative UVA cytotoxicity is a general property of DNA thiobases, and 6-thioguanine and 4-thiodeoxyuridine were also UVA sensitizers. Thiobase/UVA treatment may offer a novel therapeutic approach for the clinical management of nonmalignant conditions like psoriasis or for superficial tumors that are accessible to phototherapy.
Massey
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Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, EN6 3LD, Herts., United Kingdom.
Xu
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YZ
Karran
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P
D002460:Cell Line; D004247:DNA / Q000737:chemistry / Q000528:radiation effects*; D004260:DNA Repair; D006801:Humans; D015122:Mercaptopurine / Q000737:chemistry / Q000528:radiation effects; D010789:Phototherapy / Q000379:methods*; D013866:Thioguanine / Q000737:chemistry / Q000528:radiation effects; D013891:Thiouridine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014467:Ultraviolet Therapy; D014983:Xeroderma Pigmentosum / Q000188:drug therapy
D013891:Thiouridine; C004274:4-thio-2'-deoxyuridine; D004247:DNA; D015122:Mercaptopurine; D013866:Thioguanine