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.
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