DEVELOPMENTAL ANTIFOLATE THERAPY OF CANCER

癌症抗叶酸药物的开发治疗

基本信息

批准号：
3166762
负责人：
JAMES R. PIPER
金额：
$ 19.67万
依托单位：
SOUTHERN RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
1979
资助国家：
美国
起止时间：
1979-04-01 至 1992-03-31
项目状态：
已结题

项目摘要

The goal of the proposed research is the identification of new agents that exert greater effectiveness in the antifolate therapy of human cancer than agents now available, particularly in regard to achieving a broader spectrum of antitumor response. The proposed work is concerned with design and synthesis of potential antifolates which will be subjected to biochemical-pharmacologic evaluation. Proposed potential antifolates are designed with the aim of exploiting differences in two biochemical parameters of antifolate action in tumors and normal proliferative tissue. These differences, which appear to be determining factors for selective antitumor activity, are in cellular membrane transport and in intracellular polyglutamylation. Earlier biochemical studies which identified the 5 and 10 positions of the classical antifolate molecular structure as sites where modifications affect transport and polyglutamylation have already led to therapeutically improved antifolates of the 10-deazaaminopterin series. Studies aimed toward possible similar exploitation in the 5-deaza series of antifolates are in progress under the program whose continuation we are requesting. Recent findings that enhance our understanding of the multiple effects of classical antifolates and their intracellular polyglutamate metabolites point to the need to include compounds designed to inhibit folate-dependent sites other than dihydrofolate reductase in our quest for antifolate agents of greater effectiveness. Accordingly, in addition to compounds proposed as potential improvements over the 10-deazaaminopterin type, we also propose to prepare several attractive analogs of 10- propargyl-5,8-dideazafolic acid (CB3717) and 5,10-dideaza-5,6,7,8- tetrahydrofolic acid (DDATHF). Compound CB3717, a thymidylate synthase inhibitor, is in clinical trial; DDATHF, believed to owe its activity mainly to inhibition of glycineamide ribonucleotide transferase, has been shown to be an effective in vivo antitumor agent. Compounds synthesized in the laboratory of the applicant will be supplied to the Laboratory for Molecular Therapeutics at Sloan-Kettering Memorial Cancer Center for biological and pharmacological evaluation. Two collaborators will also receive selected samples for specialized evaluation in a coordinated program for drug evaluation in accord with the potential capability of these compounds to exert a broader spectrum of antitumor effects than methotrexate. Evaluations will include ability to inhibit tumor cell growth in vitro, dihydrofolate reductase, thymidylate synthase, AICAR transformylase, GAR transformylase, and folylpolyglutamate synthetase. Transport characteristics in tumor and gut epithelial cells will also be studied. Selected compounds will be provided for study of in vivo activity in animal tumor systems.

拟议研究的目标是确定新的药物在人类癌症的抗叶酸治疗中发挥比现在可用的代理，特别是在实现更广泛的目标方面抗肿瘤反应谱。拟议的工作涉及设计以及潜在抗叶酸剂的合成，这将受到生化药理学评价。建议的潜在抗叶酸剂是设计的目的是利用两种生物化学的差异肿瘤和正常增殖组织中抗叶酸作用的参数。这些差异似乎是选择性的决定因素抗肿瘤活性，存在于细胞膜运输和细胞内多聚谷氨酰化。早期的生化研究确定了 5 种和经典抗叶酸分子结构的 10 个位置作为位点影响运输和多聚谷氨酰化的修饰已经导致 10-脱氮氨基蝶呤系列的治疗改良抗叶酸剂。研究旨在 5-deaza 系列中可能进行类似的利用抗叶酸剂正在根据该计划进行，我们正在继续该计划要求。最近的发现增强了我们对多重因素的理解经典抗叶酸剂及其细胞内聚谷氨酸的作用代谢物表明需要包含旨在抑制的化合物在我们的探索中，除了二氢叶酸还原酶之外的叶酸依赖性位点抗叶酸剂更有效。据此，除了被提议作为 10-脱氮氨基蝶呤的潜在改进的化合物类型，我们还建议制备几种有吸引力的 10- 炔丙基-5,8-二脱氮杂叶酸 (CB3717) 和 5,10-二脱氮杂-5,6,7,8- 四氢叶酸（DDATHF）。化合物 CB3717，一种胸苷酸合酶抑制剂，正在临床试验中； DDATHF，据信归因于其活性主要是抑制甘氨酰胺核糖核苷酸转移酶被证明是一种有效的体内抗肿瘤剂。合成的化合物申请人的实验室将提供给实验室用于斯隆凯特琳纪念癌症中心的分子治疗生物学和药理学评价。两位合作者还将接收选定的样本，以协调一致的方式进行专门评估根据潜在能力制定药物评价计划这些化合物比其他化合物发挥更广泛的抗肿瘤作用甲氨蝶呤。评估将包括抑制肿瘤细胞的能力体外生长, 二氢叶酸还原酶, 胸苷酸合酶, AICAR 转化酶、GAR转化酶和叶酰聚谷氨酸合成酶。肿瘤和肠道上皮细胞的运输特性也将受到影响研究过。将提供选定的化合物用于体内活性研究在动物肿瘤系统中。