Antitumor Antimitotics That Reverse Tumor Resistance

针对微管蛋白和有丝分裂的抗分裂药物是临床上最成功的抗肿瘤药物之一。这个 长春花碱、长春新碱和长春花碱以及紫杉醇和紫杉烷是用来对抗广泛的 各种肿瘤包括白血病、霍奇金氏病、淋巴瘤(长春花碱)和乳腺、卵巢等实体瘤 肿瘤(紫杉醇和紫杉烷)。最近的证据表明，一些抗微管蛋白药物的组合具有协同作用。 目前，这种组合的临床试验正在进行中。然而，临床肿瘤耐药性是一个主要原因。 治疗失败最常见的原因是P-糖蛋白将抗肿瘤药物泵出肿瘤 细胞。因此，对耐药肿瘤有效的新型抗有丝分裂药物是人们梦寐以求的。我们最近做了 发现了一系列非常新颖的类似物，因为它们在 纳米分子范围针对抗分裂敏感和耐药的肿瘤细胞，它们结合到微管蛋白上的一个位置，即 不同于秋水仙碱、长春花碱和紫杉醇部位，还显著逆转肿瘤对抗分裂细胞的耐药性 探员们。这项提议的具体目标是：1)合成先导化合物的类似物，以提供 优化抗肿瘤活性和逆转肿瘤能力的构效关系(SAR)研究 对抗分裂药物的抗药性；2)评估这些化合物对微管和细胞周期的影响；3) 单药和联合用药的细胞毒性评价及抗多药耐药活性 这些化合物；以及4)先导化合物和选定的类似物在体内的抗肿瘤活性评价 既有抗分裂敏感肿瘤，也有耐药肿瘤。这项研究应能为设计提供一个全面的搜索结果 未来的类似物，并提供在体外和体外增强对敏感和耐药肿瘤的抗肿瘤活性的类似物 体内，以及增强的逆转肿瘤耐药性的能力，可能是在单一的药物。这样的代理可以用来 单独或与其他抗分裂或抗肿瘤药物联合使用，提供更广泛的抗肿瘤活性 既有抗分裂敏感肿瘤，也有耐药肿瘤。研究还将进一步明确小说的作用机制 系列，可以提供临床使用的药物。

Antimitotic agents that target tubulin and mitosis are some of the most clinically successful antitumor agents. The Vinca alkaloids vincristine and vinblastine as well as Taxol and the taxanes are antitubulin agents used against a wide variety of tumors including leukemias, Hodgkin's, lymphomas (Vinca alkaloids) and breast, ovarian and other solid tumors (Taxol and taxanes). Recent evidence suggests that combinations of some antitubulin agents are synergestic and clinical trials are currently underway with such combinations. Clinical tumor resistance however is a major cause of treatment failure and is most often the result of P-glycoprotein which pumps the antitumor agent out of the tumor cells. Thus novel antimitotic agents that are active against resistant tumors are highly coveted. We have recently discovered a series of analogs that are quite novel in that they possess antimitotic and antitumor activities in the nanomolar range against antimitotic sensitive as well as resistant tumor cells, they bind to a site on tubulin that is different from the colchicine, vinca alkaloid and Taxol sites, and remarkably also reverse tumor resistance to antimitotic agents. The Specific Aims of this proposal are: 1) the synthesis of analogs of the lead compounds to provide a structure-activity relationship (SAR) study to optimize both the antitumor activity as well as the ability to reverse tumor resistance to antimitotic agents; 2) evaluation of the microtubule and cell cycle effects of these compounds; 3) evaluation of the cytotoxicity both as single agents and in combination, and the anti-multidrug resistance activities of these compounds; and 4) evaluation of the in vivo antitumor activity of the lead compounds and selected analogs against both antimitotic sensitive and resistant tumors. This study should provide a comprehensive SAR for the design of future analogs and afford analogs with increased antitumor activity against sensitive and resistant tumors in vitro and in vivo as well as an increased ability to reverse tumor resistance perhaps in single agents. Such agents could be used alone or in combination with other antimitotic or antitumor agents and provide a broader spectrum of activity against both antimitotic sensitive and resistant tumors. The study will also further define the mechanism of action of the novel series and could afford agents for clinical use.