PHARMACOLOGY OF NONPOLYGLUTAMATABLE AMINOPTERIN ANALOGS

非聚谷氨酸氨基蝶呤类似物的药理学

• 批准号: 2411506
• 负责人: ANDRE ROSOWSKY
• 金额: $ 23.11万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2411506
• 关键词: aminopterin; analog; colorectal neoplasms; dihydrofolate reductase; drug interactions; drug resistance; drug screening /evaluation; enzyme activity; high performance liquid chromatography; hypoxanthines; laboratory mouse; leucovorin; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonhuman therapy evaluation; oxidoreductase inhibitor; pharmacokinetics; polyglutamates; thymidine

DESCRIPTION: (Applicant's Abstract) The overall goals of this project are to conduct in vitro and in vivo studies of the biochemical and pharmacological mode of action of a class of unusually potent water-soluble nonclassical dihydrofolate reductase inhibitors whose activity does not require, and is not dependent on, polyglutamation. The prototypical member of this class is N-alpha-(4-amino-4-deoxypteroyl)-N-delta-hemiphthaloyl-L-ornithine (PT523, NSC-633713), which was first synthesized at DFCI. Biochemical and pharmacologic properties of second generation PT523 analogs being synthesized as part of a separate chemical synthesis grant will also be investigated as part of this project with the aim of determining whether any of them may be more attractive preclinical candidates than the lead compound. Also to be studied is a recently synthesized prodrug derivative of PT523 which was designed to take advantage of "antibody directed enzyme prodrug therapy" (ADEPT) to decrease host toxicity and improve tumor versus host selectivity. Specific Aim I (in vitro studies): (i) cytotoxicity of second generation PT523 analogs from the applicant's synthesis program; (ii) prevention of cytotoxicity with thymidine and/or hypoxanthine; (iii) dihydrofolate reductase inhibition; (iii) kinetics of cellular uptake; (iv) effects on cellular reduced folate pools and on inhibition and recovery of DNA synthesis; and (v) synergistic interactions of PT523 with other, non-antifolate drugs. Specific Aim 2 (in vivo studies): (i) antitumor activity of PT523 and other second generation analogs in human xenograft tumor models; and (ii) effects on reduced folate pools and DNA synthesis inhibition/recovery in tumor versus marrow and gut. Specific Aim 3 (resistance studies): (i) in vitro production of resistance in human tumor cell lines by PT523 via different selection protocols, and comparison of the time needed to achieve a similar level of resistance to PT523 and MTX; (ii) analysis of DHFR activity and drug uptake in PT523 resistant cells, the most likely determinants of resistance to this nonpolyglutamatable drug; and iv) pilot in vitro studies on the therapeutic potential of PT523-L-Phe as the first example of an ADEPT derivatives of PT523.

描述：（申请人摘要）该项目的总体目标是 进行生物化学和体内的体外和体内研究 一类异常有效的水溶性药物的药理作用方式 非经典二氢叶酸还原酶抑制剂，其活性不 需要但不依赖于多谷氨酸。 原型成员 这个类的 N-α-(4-氨基-4-脱氧蝶酰基)-N-δ-半邻苯二甲酰基-L-鸟氨酸 (PT523, NSC-633713），首次在 DFCI 合成。 生化和 第二代 PT523 类似物的药理学特性是 作为单独的化学合成补助金的一部分合成的也将 作为该项目的一部分进行调查，旨在确定是否存在任何 其中的临床前候选者可能比领先者更具吸引力 化合物。 还有待研究的是最近合成的前药衍生物 PT523 的设计目的是利用“抗体导向酶” 前药疗法”（ADEPT）可降低宿主毒性并改善肿瘤疗效 宿主选择性。 具体目标 I（体外研究）：(i) 细胞毒性 来自申请人的合成程序的第二代PT523类似物； (二) 用胸苷和/或次黄嘌呤预防细胞毒性； (三) 二氢叶酸还原酶抑制； (iii) 细胞摄取动力学； （四） 对细胞减少的叶酸池以及对叶酸抑制和恢复的影响 DNA合成； (v) PT523 与其他药物的协同相互作用， 非抗叶酸药物。 具体目标 2（体内研究）：（i）抗肿瘤 PT523 和其他第二代类似物在人类异种移植物中的活性 肿瘤模型； (ii) 对叶酸库和 DNA 合成减少的影响 肿瘤与骨髓和肠道的抑制/恢复。 具体目标 3 （耐药性研究）：（i）人类肿瘤体外产生耐药性 PT523通过不同选择方案筛选细胞系，并比较 达到对 PT523 和 MTX 的相似耐药水平所需的时间； (二) 分析 PT523 耐药细胞中的 DHFR 活性和药物摄取，最 对这种非聚谷氨酸药物产生耐药性的可能决定因素；和四） 关于 PT523-L-Phe 作为治疗潜力的体外试验研究 PT523 的 ADEPT 衍生物的第一个示例。