EVALUATION OF CHEMOPREVENTIVE AGENTS USING A TRANSGENIC MOUSE MELANOMA MODEL

恶性黑色素瘤是一种非常侵袭性的疾病， 转移扩散的倾向。治疗是有问题的，因为 对大多数化疗方案都有抵抗力。其发病率 比肺癌以外的任何其他恶性肿瘤增长都快。在 到2000年，每100个美国人中就有1个将 发生黑色素瘤（1; 2）。毫无疑问，暴露于 太阳光谱中的紫外线B辐射有助于 疾病的发展。有必要进行机械研究， 以及干预研究，包括预防和治疗 恶性黑色素瘤的治疗缺乏动物模型， 可以在短潜伏期内可重复地诱导肿瘤， 阻碍了开发和评估实验性治疗药物的努力， 预防剂。我们提出一个解决这个问题的办法是 转基因小鼠模型，其中表达癌基因或 原癌基因以细胞特异性方式定向于黑素细胞。我们 已经制备了具有突变的人Ha-ras基因的小基因构建体， v-jun癌基因由黑素细胞特异性调节元件驱动， 酪氨酸酶启动子。转基因的表达将等同于 黑素细胞中肿瘤的发生。肿瘤促进剂与紫外线 然后，启动动物的光暴露将提供事件 对于肿瘤的促进和发展是必要的。多阶段小鼠模型 因此，黑色素瘤的发展将提供一个系统， 潜在的化学预防剂。

Malignant melanoma is a very aggressive disease which shows a high propensity for metastatic spread. Treatment is problematic because it is very resistant to most chemotherapeutic regimens. its incidence is increasing more rapidly than any other malignancy except lung cancer. At the current rate by the year 2000, 1 out of every 100 Americans will develop melanoma (l; 2). There is little doubt that exposure to the ultraviolet B radiation present in the solar spectrum contributes to development of the disease. There is a need for mechanistic studies as well as intervention studies, including prevention and treatment strategies, of malignant melanoma. The lack of an animal model in which the tumor can be reproducibly induced with a short latency period has hampered efforts to develop and evaluate experimental therapeutic and prevention agents. We propose a solution to this problem would be a transgenic mouse model in which the expression of an oncogene or protooncogene is directed in a cell specific manner to melanocytes. We have prepared minigene constructs with a mutated human Ha-ras gene and a v-jun oncogene driven by melanocyte-specific regulatory elements, the tyrosinase promoter. The expression of the transgene would be equivalent to tumor initiation in the melanocytes. Tumor promoters and ultraviolet light exposure of the initiated animals would then provide the events necessary for tumor promotion and progression. A multistage mouse model of melanoma development would thus provide a system to study the efficacy of potential chemopreventive agents.