Molecular Surrogate for Melanoma Prevention

描述(由申请人提供)： 2007年，将有6万美国人被诊断出患有黑色素瘤，其中8000人将死亡。然而，目前的防晒霜对黑色素瘤的预防是无效的，化学预防还处于起步阶段。黑色素是导致黑色素瘤的主要原因。除了保护性地吸收紫外线外，这种能量的一部分会导致反应性黑色素自由基的形成，这一过程是黑色素瘤的核心原因。因此，我们认为，测量紫外线诱导的反应性黑素自由基(UV-RMR)可以为黑色素瘤的发病机制提供一个分子替代物，因此，测量保护剂对UV-RMR的减少将为黑色素瘤的保护提供一个分子替代物。重要的是，紫外线诱导的反应性黑色素自由基所需的EPR测量可以在从分离的黑色素到活体和原位皮肤黑素细胞的各种系统中进行。因此，我们的总体假设是：保护剂抑制紫外线诱导的反应性黑素自由基形成的能力为检测黑色素瘤预防干预措施提供了一个机械基础的分子替代品。我们建议使用这项技术来研究两种互补的黑色素瘤预防策略，一种是基于防晒剂对紫外线的屏蔽以防止UV-RMR的产生，另一种是基于在UV-RMR可能造成生物损害之前对UV-RMR的新型清除。具体目的1.防晒霜降低家蝇体内UV-RMR与体内DNA氧化损伤之间的关系。这种相关性将为我们的假设提供严格的测试，即抑制UV-RMR可以提供黑色素瘤预防的替代品。具体目的2.建立一种化学预防黑色素瘤的方法，以分离的黑色素和培养的黑素细胞为模型，通过测量UV-RMR的稳态减少和UV-RMR衰减率来筛选用于清除UV-RMR的精选化合物文库。紫外线-RMR的清除与黑素细胞氧化损伤的减少相关。这项建议利用PI的独特经验，为通过物理和化学预防药物预防黑色素瘤提供了一种新的机械替代品，这种药物可能会应用于临床和体内EPR。成功完成后，我们计划在我们的动物模型中进行防晒霜和UV-RMR清除化学预防药物的体内黑色素瘤预防试验，然后在易感患者群体中进行试验。

DESCRIPTION (provided by applicant): 60,000 Americans will be diagnosed with Melanoma 2007, of whom 8,000 will die. Yet, melanoma prevention by current sunscreen is ineffective, and chemoprevention in its infancy. Melanin is central to the causation of melanoma. In addition to it protectively absorbing UV, a fraction of this energy results in the formation of reactive melanin-radicals, a process is central to melanoma causation. We therefore propose that measurement of UV induced reactive melanin-radicals (UV-RMR) can provide a mechanistically-based molecular surrogate for melanoma causation, and hence that measuring the decrease in UV-RMR by protective agents will provide a molecular surrogate of melanoma protection. Importantly, the required EPR measurements of UV induced reactive melanin-radicals can be performed in systems ranging from isolated melanin, to in vivo and in situ in melanocytes in skin. Thus, our overall hypothesis is that: The ability of protective agents to inhibit UV-induced reactive melanin radical formation provides a mechanistically-based molecular surrogate to assay melanoma prevention interventions. We propose using this technique to study two complementary strategies of melanoma prevention, one based upon UV screening by sunscreen agents to prevent UV-RMR production, the other based upon novel scavenging of UV-RMR before these can cause biological damage. Specific Aim 1. Correlate decreased UV-RMR by sunscreens in M. domestica, with decreases in oxidative DNA damage in vivo. This correlation will provide a rigorous test of our hypothesis that inhibition of UV-RMR can provide a surrogate of melanoma prevention. Specific Aim 2. Develop an assay for chemoprevention of melanoma by screening a select library of com- pounds for scavenging of UV-RMR by measuring both steady state reductions in UV-RMR and rates of UV-RMR decay, using isolated melanins and cultured melanocytes as models. Correlate scavenging of UV-RMR with decreases in oxidative damage in melanocytes. This proposal uses the PI's unique experience to provide a new mechanistic surrogate for melanoma prevention by both physical and chemopreventive agents that can potentially be applied clinically with in vivo EPR. Upon successful completion, we plan to perform in vivo melanoma prevention trials of sunscreen and UV-RMR scavenging chemopreventive agents in our animal models, and then in susceptible patient populations.