Novel anti-melanoma agents and their mechanism of action

描述(由申请人提供)：黑色素瘤的发病率继续急剧上升，现有的化疗策略对转移性黑色素瘤几乎没有效果。恶性黑色素瘤被认为是一种化疗难治性肿瘤。目前，达卡巴津是唯一最有效的抗黑色素瘤药物，但有效率较低，约为20%。即使是将达卡巴津与卡莫司汀、顺铂和三苯氧胺相结合的达卡莫斯方案等联合疗法，也只取得了40%的有效率(Nathan等人，2000年)。仅紫杉醇(R)已显示出16%的有效率，但有相当大的毒性，包括剂量限制的中性粒细胞减少症和周围神经病变(Nathan等人，2000年)。出于这些原因，需要更有效和耐受性更好的化疗药物。基于与微管毒素(秋水仙碱、鬼臼毒素，MTC)的结构相似性，我们确定了一种与微管蛋白结合的天然化合物noscape ine(Ye等人，1998)。我们的初步研究表明，诺斯汀在体外对黑色素瘤、前列腺癌和结肠癌细胞具有选择性有效的治疗作用。我们提出了以下三个目标。目的1利用高分辨率核磁共振和自动对接算法研究诺伐他汀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将比较诺伐他汀类似物与其他目前使用的微管制剂泰素(R)、长春花碱和长春瑞滨治疗前列腺癌和结肠癌的相对疗效和毒性。这些临床前研究对于这类有前景的治疗化合物的未来临床开发将是至关重要的。

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.