TOPS-Ester Modulation of UVB-Induced Immune Suppression

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DESCRIPTION (provided by applicant): A TOPS-ester, diethyl 2,2,6,6-tetramethyl-1-oxyl-4-piperidene succinate (DETOPS), is a topical drug selected for development for its unique ability to compartmentalize within skin cells and express antioxidant activity that limits oxidant mediated pathologies including psoriasis, sunburn, skin aging and skin cancer. The objective of this project is to reduce skin cancer by preventing UV radiation-induced immune suppression. The specific aim of this study is to test the capability of DETOPS to interfere with the suppression of the immune system in mice that normally follows biologically-relevant doses of UV radiation. The immune status of SKH-1 hairless mice will be assessed by measuring whether topical application of DETOPS alters UV radiation induced changes in contact hypersensitivity. UV exposed control and DETOPS treated animals will be sensitized by topical application of dinitrofluorobenzene (DNFB) to their unirradiated abdomens. The animals will be challenged six days after sensitization by topical application of DNFB to ears. The magnitude of the ear-swelling response will be measured 15-21 hours later. A reduction in ear-swelling normally results from UV radiation-induced immunosuppression. The capacity of DETOPS to prevent skin cancer will be assessed in SKH-1 hairless mice chronically exposed to a biologically-relevant dose of UV radiation. Groups of mice with and without DETOPS treatment will be exposed to UV radiation five days per week for 11 weeks and then monitored for an additional 13 weeks for the appearance of skin tumors. The endpoints of interest for this study are whether DETOPS retards the time to appearance of skin cancer and reduces the yield of tumors. The immune status and skin cancer experiments will be supported by following DETOPS metabolism via pharmacokinetic and pharmacodynamic studies.