BIOCHEMICAL PHARMACOLOGY OF ANTINEOPLASTIC AGENTS

抗肿瘤药物的生化药理学

• 批准号: 3163107
• 负责人: ALAN CLAYTON SARTORELLI
• 金额: $ 52.37万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-01-01 至 1990-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3163107
• 关键词: antineoplastics; drug design /synthesis /production; drug metabolism; neoplasm /cancer pharmacology

The objectives of the proposed research are to develop therapeutic drug regimens that will have use in he treatment of cancer in man on the basis of pharmacological and biochemical information on the mechanism of drug action, with particular emphasis on (a) characterization of the metabolic alterations responsible for cell death following exposure to chemical stress, (b) exploitation of possible neoplastic cellular sites of vulnerability by chemical modification of existing agents having some clinical efficacy, as well as further design and synthesis of new drugs based upon biochemical and pharmacological principles, and (c) the selection, on the basis of metabolic action, of drugs to employ in combination, thereby gaining increased therapeutic efficacy. Research emphasis is being placed upon the following: (a) quinone imides, quinones, chromones and nitro-containing bioreductive alkylating agents with preferential cytotoxicity for hypoxic cells; (b) alpha-(N)-heterocyclic carboxaldehyde thiosemicarbazones, in an effort to develop a second generation inhibitor of ribonucleotide reductase with clinical potential; (c) tetramisole derivatives as inhibitors of alkaline phosphohydrolase and the mechanism by which neoplastic cells attain resistance to the 6-thiopurines; (d) development and study of the biochemical mechanism of action of arylsulfonylhydrazones of pyridine N-oxide as anticancer drugs; (e) effects of anticancer agents and other metabolic inhibitors on surface membranes of neoplastic cells stressing the action of 6-thioguanine and 2-deoxy-D-glucose; (f) role of glycosaminoglycans in muring melanoma metastases, and the development of antimetastatic agents; (g) studies on the comparative action of 2'-azido-2'-deoxy-beta-D-arabinofuranosyladenine and arabinosyladenine; and (h) the mechanism by which 6-thioguanine and certain anthracyclines induce the differentiation of leukemic cells.

该研究的目的是开发治疗药物 将用于治疗人类癌症的方案， 药物作用机制的药理学和生物化学信息 作用，特别强调（a）代谢的表征 改变负责细胞死亡后暴露于化学品 应激，（B）利用可能肿瘤细胞位点， 化学改性的现有制剂具有一些 临床疗效，以及新药的进一步设计和合成 基于生物化学和药理学原理，以及（c） 在代谢作用的基础上选择药物用于 组合，从而获得增加的治疗功效。 研究 重点放在以下方面：（a）醌酰亚胺，醌， 色酮和含硝基的生物还原性烷基化剂， 对缺氧细胞的优先细胞毒性;（B）α-（N）-杂环 甲醛缩氨基硫脲，努力开发第二个 具有临床潜力的核苷酸还原酶生成抑制剂; (c)作为碱性磷酸水解酶抑制剂的四咪唑衍生物和 肿瘤细胞获得对肿瘤细胞的抵抗的机制， 6-硫嘌呤;（d）开发和研究 吡啶N-氧化物的芳基磺酰腙作为抗癌药物的作用; (e)抗癌剂和其他代谢抑制剂对表面的影响 肿瘤细胞膜强调6-硫鸟嘌呤的作用， 2-脱氧-D-葡萄糖;（f）糖胺聚糖在黑色素瘤中的作用 （g）关于癌症转移的研究，以及抗转移药物的开发; 2 ′-叠氮基-2 ′-脱氧-β-D-阿拉伯呋喃糖基腺嘌呤作用比较 和阿拉伯糖基腺嘌呤;以及（h）6-硫代鸟嘌呤和 某些蒽环类药物诱导白血病细胞分化。