ABSTRACT
The molecular basis for ultraviolet (UV) light-induced nonmelanoma and melanoma skin cancers centers on cumulative genomic instability caused by inefficient DNA repair of dipyrimidine photoproducts. Inefficient DNA repair and subsequent translesion replication past these DNA lesions generate distinct molecular signatures of tandem CC to TT and C to T transitions at dipyrimidine sites. Since previous efforts to develop experimental strategies to enhance the repair capacity of basal keratinocytes have been limited, we have engineered the N-terminally truncated form (Δ228) UV endonuclease (UVDE) from Schizosaccharomyces pombe to include a TAT cell-penetrating peptide sequence with or without a nuclear localization signal (NLS): UVDE-TAT and UVDE-NLS-TAT. Further, a NLS was engineered onto a pyrimidine dimer glycosylase from Paramecium bursaria chlorella virus-1 (cv-pdg-NLS). Purified enzymes were encapsulated into liposomes and topically delivered to the dorsal surface of SKH1 hairless mice in a UVB-induced carcinogenesis study. Total tumor burden was significantly reduced in mice receiving either UVDE-TAT or UVDE-NLS-TAT versus control empty liposomes and time to death was significantly reduced with the UVDE-NLS-TAT. These data suggest that efficient delivery of exogenous enzymes for the initiation of repair of UVB-induced DNA damage may protect from UVB induction of squamous and basal cell carcinomas.
Subject(s)
Carcinogenesis/radiation effects , DNA Repair , Skin Neoplasms/prevention & control , Ultraviolet Rays , Animals , DNA Repair Enzymes/administration & dosage , DNA Repair Enzymes/genetics , DNA Repair Enzymes/metabolism , Mice, Hairless , Recombinant Proteins/administration & dosage , Recombinant Proteins/genetics , Recombinant Proteins/metabolismABSTRACT
BACKGROUND: Recent animal and human studies have suggested that the therapeutic benefit of methotrexate in the treatment of rheumatoid arthritis may be substantially reduced in patients who are concomitantly consuming caffeine. Here, we aimed to investigate the effect of caffeine consumption on the methotrexate dosing requirements in patients with psoriasis and psoriatic arthritis. METHODS: One hundred and fifty patients with diagnoses of psoriasis or psoriatic arthritis were surveyed for their current weekly methotrexate dosage and their usual daily consumption of caffeine. RESULTS: Seventy-five of the patients given the survey responded; of these, 11 were eliminated because they did not report their methotrexate dosage or were no longer taking methotrexate. Of the remaining 64 patients, no correlation was found between the methotrexate dosage needed for disease maintenance and the amount of caffeine consumed. CONCLUSIONS: Our findings suggest that caffeine does not affect methotrexate dosage requirements in patients with psoriasis and psoriatic arthritis. These results do not rule out an effect of caffeine in other inflammatory diseases treated with methotrexate.
