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: 7192449
• 负责人: ALEEM GANGJEE
• 金额: $ 24.79万
• 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 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7192449
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; ABCC1 gene; Antimitotic Agents; Binding; Binding Sites; Biological; Breast; Cell Cycle; Chromosomes; Clinical; Clinical Trials; Colchicine; Complement component C1s; Digit structure; Dose; Evaluation; Excision; Future; Goals; Hodgkin Disease; In Vitro; Inhibitory Concentration 50; Knowledge; Lead; Lymphoma; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Medicine; Microtubules; Mitosis; Modeling; Multi-Drug Resistance; Ovarian; P-Glycoprotein; P-Glycoproteins; Paclitaxel; Parents; Pennsylvania; Pharmacology; Play; Principal Investigator; Process; Property; Protein Overexpression; Proteins; Pump; Pyrimidine; Pyrimidines; Range; Research Personnel; Resistance; Role; Series; Site; Solid Neoplasm; Structure; Structure-Activity Relationship; Taxane Compound; Toxic effect; Treatment Failure; Tubulin; Tumor Cell Line; Universities; Vinblastine; Vinca Alkaloids; Vincristine; Work; analog; antitumor agent; base; chemotherapeutic agent; college; cytotoxicity; daughter cell; design; in vivo; leukemia; neoplastic cell; novel; polymerization; programs; taxane; tumor

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）：靶向微管蛋白和有丝分裂的抗魔法剂是临床上最成功的抗肿瘤剂。 VINCA生物碱长春蛋白和葡萄醇以及紫杉醇和紫杉烷都是抗蛋白酶药物，用于针对多种肿瘤，包括白血病，霍奇金，淋巴瘤，淋巴瘤（VINCA碱类生物碱）以及乳腺癌，卵巢，卵巢和其他实体瘤和其他实体瘤和其他实体瘤（紫菜和紫杉醇）。最近的证据表明，某些抗维蛋白剂的组合是协同作用，目前正在进行此类组合进行临床试验。然而，临床肿瘤耐药性是治疗衰竭的主要原因，通常是P-糖蛋白的结果，该蛋白会从肿瘤细胞中泵出抗肿瘤剂。因此，活跃于抗性肿瘤的新型抗解剂是高度令人垂涎的。我们最近发现了一系列非常新颖的类似物，因为它们在纳摩尔中具有抗魔法和抗肿瘤活性，范围与抗杀菌敏感性和耐药性肿瘤细胞具有与微管蛋白上的位点结合，该位点与哥尔甲蛋白酶，VINCA碱基和紫杉醇位点不同，并且异常反向抗肿瘤抗菌剂，它们与甲状腺菌属，VINCA碱基和紫杉醇相反。该提案的具体目的是：1）铅化合物的类似物的合成，以提供结构活性关系（SAR）研究，以优化抗肿瘤活性以及对抗魔法剂的抗性抗肿瘤的能力； 2）评估这些化合物的微管和细胞周期效应； 3）评估细胞毒性是单一药物和组合，以及这些化合物的抗杀菌性抗性活性； 4）评估铅化合物的体内抗肿瘤活性，并选择对抗魔法敏感和抗性肿瘤的类似物。这项研究应为未来的类似物的设计提供全面的SAR，并为对敏感和抗性肿瘤在体外和体内的抗肿瘤活性增加，以及在单个药物中逆转肿瘤抗性的能力增加。此类药物可以单独使用，也可以与其他抗魔法或抗肿瘤剂结合使用，并提供针对抗魔法敏感和耐药性肿瘤的更广泛的活性。这项研究还将进一步定义新型系列的作用机理，并可以为临床用途提供代理。