Novel anti-melanoma agents and their mechanism of action

描述（由申请人提供）：黑色素瘤的发病率持续急剧上升，现有的化疗策略对转移性黑色素瘤的疗效甚微。恶性黑色素瘤被认为是一种化疗难治性肿瘤。目前，达卡巴嗪是抗黑色素瘤最有效的单一药物，但反应率很低，约为20%。即使是联合治疗，如达特茅斯方案，将达卡巴嗪与卡莫司汀、顺铂和他莫昔芬联合使用，也只能达到40%的缓解率（Nathan et al., 2000）。单独使用紫杉醇(R)的有效率为16%，但具有相当大的毒性，包括剂量限制性中性粒细胞减少症和周围神经病变（Nathan et al, 2000）。由于这些原因，需要更有效和耐受性良好的化疗药物。基于与微管毒物（秋水仙碱、鬼臼毒素、MTC）的结构相似性，我们确定了一种微管蛋白结合的天然化合物，诺斯卡平（Ye et al., 1998）。我们的初步研究表明，诺斯卡平对体外治疗黑色素瘤、前列腺癌和结肠癌细胞有选择性有效。我们提出以下三个目标。目的1提出利用高分辨率核磁共振和自动对接算法研究诺斯卡平与微管蛋白的结合机制。目的2将确定生物分布、最佳治疗剂量和可能的毒性。目的3将比较诺斯卡平类似物与其他目前使用的微管药物，紫杉醇(R)，长春花碱和长春瑞滨在前列腺癌和结肠癌中的相对疗效和毒性。这些临床前研究对于这类有前景的治疗性化合物的未来临床开发至关重要。

DESCRIPTION (provided by applicant): The incidence of melanoma continues to dramatically rise and existing chemotherapeutic strategies have shown little effect against metastatic melanoma. Malignant melanoma is considered a chemotherapy refractory tumor. Currently dacarbazine is the single most active agent against melanoma but has a low response rate of approximately 20%. Even combination therapy such as the Dartmouth regimen, which combines dacarbazine with carmustine, cisplatin, and tamoxifen, achieves a response rate of only 40% (Nathan et al., 2000). Taxol(R) alone has shown a 16% response rate but has considerable toxicity including dose limiting neutropenia as well as peripheral neuropathy (Nathan et al., 2000). For these reasons, more effective and well-tolerated chemotherapeutic agents are needed. Based upon structural similarities to microtubule poisons (colchicine, podophylotoxin, MTC), we identified a tubulin binding natural compound, noscapine (Ye et al., 1998). Our preliminary studies show that noscapine is selectively effective for the treatment of melanoma, prostate, and colon cancer cells in vitro. We propose the following three aims. Aim 1 proposes studies to understand the binding mechanisms of noscapine with tubulin using high resolution NMR and automated docking algorithms. Aim 2 will determine the bio-distribution, optimal therapeutic dose, and possible toxicity. Aim 3 will compare the relative efficacy and toxicity of the noscapine analogs with those of other currently used microtubule agents, Taxol(R), vinblastine, and vinorelbine in prostate and colon cancers. These preclinical studies will be crucial for the future clinical development of this class of promising therapeutic compounds.