TOPS-Ester Modulation of UVB-Induced Immune Suppression

UVB 诱导的免疫抑制的 TOPS 酯调节

• 批准号: 6550150
• 负责人: Carleton Hsia
• 金额: $ 9.87万
• 依托单位: SYNZYME TECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6550150
• 关键词: antioxidants; cancer prevention; drug metabolism; drug screening /evaluation; free radical oxygen; hairless mouse; immunoregulation; nitrobenzene; radiation immunosuppression; skin hypersensitivity; skin neoplasms; topical drug application; ultraviolet radiation

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.

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.该项目的目的是通过防止紫外线辐射诱导的免疫抑制来减少皮肤癌。这项研究的具体目的是测试Desop的能力，干扰通常遵循生物学上与紫外线相关的紫外线辐射的小鼠中免疫系统的抑制。 SKH-1无毛小鼠的免疫状态将通过测量局部应用​​是否会改变紫外线辐射引起的接触过敏性变化来评估。通过将二硝基氟苯（DNFB）局部应用在其未经侵蚀的腹部中，将紫外线暴露的控制和破坏治疗的动物敏感。通过将DNFB局部应用到耳朵的局部应用后六天后，这些动物将受到挑战。 15-21小时后，将测量耳塞响应的大小。通常是由于紫外线辐射诱导的免疫抑制而导致的，通常会导致耳朵呆滞。 在SKH-1无毛小鼠中，将评估DETOP预防皮肤癌的能力，该小鼠长期暴露于与生物学上与紫外线相关的紫外线辐射中。接受和不进行干燥治疗的小鼠组将暴露于每周五天的紫外线辐射11周，然后对皮肤肿瘤的出现进行另外13周的监测。这项研究感兴趣的终点是Detop是否阻碍了皮肤癌出现的时间并降低肿瘤的产量。 免疫状态和皮肤癌实验将通过通过药代动力学和药效研究来支持Datops代谢来支持。