FOLYLPOLYGLUTAMATE SYNTHETASE IN CANCER CHEMOTHERAPY

叶酰聚谷氨酸合成酶在癌症化疗中的应用

• 批准号: 3185687
• 负责人: JOHN J MCGUIRE
• 金额: $ 9.11万
• 依托单位: ROSWELL PARK CANCER INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-05-01 至 1992-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3185687
• 关键词: aminoacid; aminopterin; antileukemic agent; cell bank /registry; cofactor; drug design /synthesis /production; enzyme inhibitors; folate antagonist; glutamates; hypoxanthines; leukemia; ligase; methotrexate; ornithine; polyglutamates; thymidine

The long-term goal of this research is to develop improved agents or strategies for the treatment of human cancer by exploiting aspects of folyl or antifolylpolyglutamate synthesis. Folypolyglutamates are essential for viability and proliferation; polyglutamates of classical antifolates are implicated in the cytotoxic mechanism of these agents. Synthesis of polyglutamates plays a role in drug resistance and may also have a role in selectivity. Complete understanding of the synthesis and function of folyl- and antifolylpolyglutamates may expedite the development of new agents to exploit this critical pathway. This goal will be addressed through the following specific aims: (1) design and characterization of inhibitors of folypolyglutamate synthetase (FPGS), the enzyme which synthesizes polyglutamates. Rational design of these agents is based on FPGS substrate specificity and inhibitor data generated in this lab. Syntheses will be performed by collaborators. Characterization of the agents will be performed in this lab. Several classes of FPGS inhibitors are proposed, including (a) analogs of the only known, human FPGS- specific inhibitor, 5,8-dideazapteroylornithine (Dr. Piper) and (b) the gamma-tetrazole folate analogs (Dr. Kalman) which seem to be well transported; (2) use of FPGS inhibitors in the investigation of polyglutamate metabolism and regulation in whole cells. Basic knowledge derived from such studies may allow the more effective use of current antifols or suggest new targets for therapeutic intervention; (3) characterize existing human leukemia cell sub- lines which are resistant to MTX solely because of decreased MTX polyglutamate (MTXGn) synthesis. These lines are unique both in their clinically relevant selection method and the fact that they apparently have no other mechanisms of resistance. One of these lines contains an altered FPGS; this is the only description of MTX resistance due to an altered FPGS. Since decreased MTXGn synthesis has been identified clinically in acquired resistance to MTX, this cell line presents an opportunity to characterize this phenotype and to design therapeutic strategies to overcome this type of resistance. Comparison of the enzymatic properties of the native and altered FPGS will also provide information which will aid design of FPGS inhibitors.

这项研究的长期目标是开发改进的试剂。 或通过开发治疗人类癌症的策略 叶基或反叶基聚谷氨酸合成方面。 多聚谷氨酸盐对细胞的存活和增殖是必不可少的； 经典的抗叶酸的多谷氨酸与 这些药物的细胞毒作用机制。聚谷氨酸酯的合成 在耐药中起作用，也可能在 选择性。对其合成和功能有完整的理解 叶基和反叶基多谷氨酸盐可能会加速发育 利用这一关键途径的新药物。 这一目标将通过以下具体目标来实现： (1)叶多聚谷氨酸抑制剂的设计与表征 合成酶(FPGS)，合成多谷氨酸的酶。 这些制剂的合理设计是基于FPGS底物的 在本实验室中生成的特异性和抑制剂数据。合成 将由合作者执行。试剂的表征 将在本实验中执行。几类FPGS抑制剂 包括：(A)已知的唯一的人类FPGS的类似物- 特定的抑制剂，5，8-二氮杂蝶酰鸟氨酸(派珀博士)和(B) 伽马-四氮唑叶酸类似物(卡尔曼博士) 转运良好；(2)在研究中使用FPGS抑制剂 多聚谷氨酸在整个细胞中的代谢和调节。基本信息 从这类研究中获得的知识可能会使 使用现有的抗抗体或建议新的治疗靶点 干预；(3)表征现有的人类白血病细胞亚群 仅因MTX降低而对MTX产生抗性的品系 聚谷氨酸(MTXGn)合成。这些线路在两个方面都是独一无二的 他们的临床相关选择方法以及他们 显然没有其他抵抗机制。这其中的一个 LINES包含更改后的FPGS；这是对MTX的唯一描述 由于FPGS改变而产生的抵抗力。由于MTXGn合成减少 已经在临床上被确认为对MTX的获得性耐药，这 细胞系提供了一个表征这种表型的机会 并设计治疗策略来克服这种类型的 抵抗。天然大豆分离蛋白的酶学性质比较 而改变后的FPGS也将提供有助于 FPGS抑制剂的设计。