NOVEL COMPOUNDS WHICH CIRCUMVENT MULTIDRUG RESISTANCE

规避多药耐药性的新型化合物

• 批准号: 6074696
• 负责人: CHARLES D. SMITH
• 金额: $ 22.97万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-02-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6074696
• 关键词: P glycoprotein; SCID mouse; amides; antineoplastics; biological products; computer simulation; cytotoxicity; disease /disorder model; drug design /synthesis /production; drug metabolism; drug screening /evaluation; laboratory rat; membrane transport proteins; multidrug resistance; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; pharmacokinetics; protein binding; quinoxalines; tissue /cell culture

DESCRIPTION: (Applicant's Abstract) Current cancer chemotherapy programs often provide temporary clinical improvement; however, tumors which survive the initial therapeutic attack often recover with increased resistance to many structurally unrelated drugs. This phenomenon is termed multidrug resistance (MDR), and is often mediated by increased expression of proteins which act as drug efflux pumps, such as P-glycoprotein and MRP. It is believed that compounds which antagonize these pumps could be used to impair the expansion of MDR cells, and so would be of enormous therapeutic value. Unfortunately, no compounds have yet proven to have clinical utility as MDR reversing agents. The overall goal of this project is to identify and characterize new compounds which are able to selectively overcome MDR. The applicant's studies have identified several new natural products and synthetic compounds that circumvent transporter-mediated multiple drug resistance in vitro. These studies have also led the generation of the hypothesis that selectivity of antagonism toward either P-glycoprotein or MRP is highly desirable for new clinical agents. Studies described herein will seek to maximize this selectivity through computer-aided design of novel anti-MDR compounds. Further assessment of the potential clinical utility of these compounds depends on in vivo testing in animal models of MDR. To attempt to mimic the clinical situation, the applicant will use xenografts of P-glycoprotein- and MRP-overexpressing cells in mice, and to determine the abilities of these agents to selectively reverse MDR in vivo. When appropriate, the mechanism of reversal will be explored by examination of the pharmacokinetics and disposition of the modulators and selected anticancer drugs. These studies should allow a critical evaluation of the potential utility of these novel compounds as clinical agents.

描述：（申请人摘要）当前癌症化疗方案 经常提供暂时的临床改善；然而，存活下来的肿瘤 最初的治疗攻击通常会随着抵抗力的增加而恢复 许多结构上不相关的药物。 这种现象被称为多药 耐药性（MDR），通常由蛋白质表达增加介导 充当药物外排泵，例如 P-糖蛋白和 MRP。 这是 相信拮抗这些泵的化合物可以用来削弱 MDR 细胞的扩增，因此具有巨大的治疗价值。 不幸的是，尚未证明任何化合物具有 MDR 的临床效用 逆转剂。 该项目的总体目标是确定和 表征能够选择性克服 MDR 的新化合物。 这 申请人的研究已经确定了几种新的天然产物和 规避转运蛋白介导的多种药物的合成化合物 体外耐药性。 这些研究也导致了 假设对 P-糖蛋白或 MRP 对于新的临床药物来说是非常理想的。 本文描述的研究 将寻求通过计算机辅助设计来最大化这种选择性 新型抗MDR化合物。 进一步评估潜在的临床 这些化合物的效用取决于动物模型的体内测试 耐多药。 为了尝试模仿临床情况，申请人将使用 P-糖蛋白和 MRP 过表达细胞在小鼠体内的异种移植物，以及 确定这些药物在体内选择性逆转 MDR 的能力。 在适当的时候，将通过检查来探索逆转的机制 调节剂的药代动力学和配置以及所选的 抗癌药物。 这些研究应该允许对 这些新型化合物作为临床药物的潜在用途。