? ? 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. ? ? ?
