Resveratrol and Human Melanoma

描述（由申请人提供）： 黑色素瘤的发病率在美国人口中迅速增加。在35岁以下的人口中，它是所有癌症类型中发病率和死亡率最高的。一旦黑色素瘤发展到侵袭性阶段，就很难治愈，因为有效的化疗药物很少。我们发现，葡萄皮、某些坚果，尤其是红酒中含有的植物多酚白藜芦醇，是两种人类黑色素瘤细胞系凋亡的有效诱导剂。我们建议测试的假设，白藜芦醇可以抑制发展/生长的人黑色素瘤裸鼠移植瘤。这将通过三个目标进行研究。首先，我们将确定在肿瘤细胞接种前饮食给予白藜芦醇是否可以延缓黑色素瘤的发生。我们还将研究白藜芦醇的饮食管理是否可以抑制已经建立的黑色素瘤异种移植物的生长。如果饮食给药没有效果，那么我们将确定是否直接注射白藜芦醇到肿瘤部位可以抑制黑色素瘤异种移植物的生长。第二个目的是研究白藜芦醇在无胸腺小鼠体内的代谢及其主要代谢产物。将特别强调白藜芦醇或代谢物在皮肤和肿瘤中的积累。最后，我们将开始研究白藜芦醇诱导人黑色素瘤细胞系凋亡的分子机制，通过使用抗肿瘤特异性基因阵列方法结合抗肿瘤特异性抗体阵列。这些实验应该提供数据，以显示白藜芦醇是否可能是一种有效的体内化学预防/治疗剂。此外，从代谢和分子机制研究中获得的信息可以为改善/最大化白藜芦醇的生物活性提供见解。

DESCRIPTION (provided by applicant): The incidence of melanoma is rapidly increasing in the U.S. population. Within the under-35 age population, it has the highest incidence and mortality of all cancer types. Once melanoma has progressed to the invasive stage, it is difficult to cure, since there are very few effective chemotherapeutic agents. We have found that the plant polyphenol, resveratrol, present in grape skins, certain nuts and especially red wine, is a potent inducer of apoptosis in two human melanoma cell lines. We propose to test the hypothesis that resveratrol can inhibit the development/growth of human melanoma xenografts in nude mice. This will be investigated by three aims. First, we will determine if dietary administration of resveratrol prior to tumor cell inoculation can delay the onset of melanoma development. We will also investigate whether dietary administration of resveratrol can inhibit the growth of already established melanoma xenografts. If dietary administration has no effect, then we will determine if direct injection of resveratrol into the tumor site can inhibit melanoma xenograft growth. In the second aim we will investigate the metabolism of resveratrol and characterize its major metabolites in the athymic mouse. Special emphasis will be placed on the accumulation of resveratrol or metabolites in the skin and in the tumors. Lastly, we will begin studies on the molecular mechanism by which resveratrol induces apoptosis in human melanoma cell lines by using an apoptotic-specific gene array approach combined with a apoptotic-specific antibody array. These experiments should provide data to show whether resveratrol might be an effective in vivo chemo-preventive/therapeutic agent. Also the information derived from the metabolism and molecular mechanism studies could provide insights into improving/maximizing the biological activity of resveratrol.