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.

描述(申请人提供)：一种TOPS-酯，2，2，6，6-四甲基-1-氧基-4-哌啶烯琥珀酸二乙酯(DETOPS)，是一种选择开发的外用药物，因为它具有在皮肤细胞内分隔和表达抗氧化活性的独特能力，可以限制氧化介导的病理，包括牛皮癣、晒伤、皮肤老化和皮肤癌。该项目的目标是通过预防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DETOPS干预正常情况下生物相关剂量的紫外线辐射对小鼠免疫系统的抑制的能力。 SKH-1无毛小鼠的免疫状态将通过测量局部应用DETOPS是否改变紫外线辐射引起的接触超敏反应的变化来评估。紫外线照射对照组和DETOPS处理组动物将通过在其未照射的腹部局部应用二硝基氟苯(DNFB)来致敏。致敏六天后，动物将接受耳朵局部应用DNFB的挑战。耳朵肿胀反应的大小将在15-21小时后测量。耳朵肿胀的减轻通常是由于紫外线辐射诱导的免疫抑制。 DETOPS预防皮肤癌的能力将在长期暴露于生物相关剂量的紫外线辐射的SKH-1无毛小鼠身上进行评估。每组接受和不接受DETOPS治疗的小鼠将每周暴露于紫外线辐射下，每周五天，持续11周，然后再监测13周，以观察皮肤肿瘤的出现。这项研究的终点是DETOPS是否延缓了皮肤癌的出现时间，并减少了肿瘤的产生。 免疫状态和皮肤癌实验将通过药代动力学和药效学研究得到后续DETOPS代谢的支持。