Antitumor Antimitotics That Reverse Tumor Resistance

逆转肿瘤耐药性的抗肿瘤抗有丝分裂药

• 批准号: 7031069
• 负责人: ALEEM GANGJEE
• 金额: $ 25.53万
• 依托单位: DUQUESNE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-24 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7031069
• 关键词: analog; antimitotics; neoplasm /cancer

DESCRIPTION (provided by applicant): 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 synergistic 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.

描述(由申请人提供)：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。长春花碱、长春新碱和长春花碱以及紫杉醇和紫杉烷都是用于治疗多种肿瘤的抗微管蛋白药物，包括白血病、霍奇金氏病、淋巴瘤(长春花碱)以及乳腺、卵巢和其他实体肿瘤(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，目前正在对这些组合进行临床试验。然而，临床肿瘤耐药性是治疗失败的主要原因，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。我们最近发现了一系列非常新颖的类似物，它们对抗分裂敏感和耐药的肿瘤细胞具有纳摩尔范围的抗分裂和抗肿瘤活性，它们与微管蛋白上不同于秋水仙碱、长春花碱和紫杉醇的位点结合，并显著逆转肿瘤对抗分裂药物的耐药性。本建议的具体目的是：1)合成先导化合物的类似物以提供构效关系(SAR)研究以优化抗肿瘤活性以及逆转肿瘤对抗分裂药耐药性的能力；2)评估这些化合物的微管和细胞周期影响；3)评估作为单一药物和联合使用的细胞毒性，以及这些化合物的抗多药耐药活性；以及4)评价这些先导化合物和选定的类似物对抗细胞分裂敏感和耐药肿瘤的体内抗肿瘤活性。这项研究将为未来类似物的设计提供一个全面的SAR，并提供类似物在体内外对敏感和耐药肿瘤具有更强的抗肿瘤活性，以及增强逆转肿瘤耐药性的能力，可能是在单一药物中。这些药物可以单独使用，也可以与其他抗分裂或抗肿瘤药物联合使用，对抗分裂敏感和耐药肿瘤提供更广泛的活性。这项研究还将进一步确定新系列药物的作用机制，并可能为临床使用提供药物。