FOLYLPOLYGLUTAMATE SYNTHETASE IN CANCER CHEMOTHERAPY

这项研究的长期目标是开发改进的代理商 或者说是通过利用 叶酰或抗叶酰聚谷氨酸合成的方面。 多聚谷氨酸盐对生存力和增殖至关重要; 经典抗叶酸剂的聚谷氨酸盐与 这些药物的细胞毒性机制。 聚谷氨酸酯的合成 在耐药性中起作用，也可能在 选择性 完全理解合成和功能 叶酸和抗叶酸聚谷氨酸盐可能会加速发展 来开发这一关键途径。 将通过以下具体目标实现这一目标： (1)叶酸聚谷氨酸抑制剂的设计与表征 合成酶（FPGS），合成聚谷氨酸的酶。 这些试剂的合理设计是基于FPGS底物 特异性和抑制剂数据。 合成 将由合作者执行。 制剂的表征 将在本实验室进行。 几类FPGS抑制剂 提出，包括（a）唯一已知的人FPGS的类似物- 特异性抑制剂，5，8-二脱氮杂蝶酰鸟氨酸（Dr. Piper）和（B） γ-四唑叶酸类似物（卡尔曼博士），似乎是 运输良好;（2）在研究中使用FPGS抑制剂 在整个细胞中的多聚谷氨酸代谢和调节。 基本 从这些研究中获得的知识可以使更有效的 使用现有的抗叶酸剂或提出新的治疗靶点 干预;（3）表征现有人白血病细胞亚群， 仅由于MTX降低而对MTX耐药的品系 聚谷氨酸（MTXGn）合成。 这些线是独一无二的， 他们的临床相关的选择方法和事实， 显然没有其他抵抗机制。 其中一 行包含改变的FPGS;这是MTX的唯一描述 由于FPGS的改变而产生的阻力。 由于MTXGn合成减少 在临床上已被确定为对MTX的获得性耐药， 细胞系提供了表征这种表型的机会 并设计治疗策略来克服这种类型的 阻力 天然的酶性质的比较 和改装的FPGS也将提供信息， FPGS抑制剂的设计。

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.