EVALUATION OF CHEMOPREVENTIVE AGENTS USING A TRANSGENIC MOUSE MELANOMA MODEL

恶性黑色素瘤是一种侵袭性很强的疾病。 转移扩散的倾向。治疗是有问题的，因为它 对大多数化疗方案都有很强的抗药性。它的发病率是 增长速度比除肺癌以外的任何其他恶性肿瘤都要快。在… 按照目前的速度，到2000年，每100名美国人中就有1人 发展为黑色素瘤(L；2)。毫无疑问，接触到 太阳光谱中存在的紫外线B辐射有助于 疾病的发展。有必要进行机械论研究，因为 以及干预研究，包括预防和治疗 恶性黑色素瘤的治疗策略。缺乏一种动物模型 该肿瘤可以在短潜伏期内被重复地诱导 阻碍了开发和评估实验性治疗和 防御剂。我们建议这个问题的解决方案是 转基因小鼠模型，在该模型中癌基因或 原癌基因以一种细胞特有的方式定向到黑素细胞。我们 已经准备了带有突变的人Ha-ras基因的微型基因构建物，并 由黑素细胞特异性调控元件驱动的v-jun癌基因 酪氨酸酶启动子。转基因的表达将等同于 与黑素细胞的肿瘤启动有关。肿瘤促进剂与紫外线 被启动的动物的光照将提供这些事件 对肿瘤的促进和发展是必要的。一种多阶段小鼠模型 因此，黑色素瘤的发展将提供一种研究疗效的系统 潜在的化学预防药物。

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.