BIOCHEMICAL PHARMACOLOGY OF ANTINEOPLASTIC AGENTS

拟议研究的目标是开发治疗药物。 将在人类癌症治疗的基础上使用的方案 关于药物作用机制的药理和生化信息 行动，特别强调(A)代谢的特征 接触化学物质后导致细胞死亡的改变 应激，(B)开发可能的肿瘤细胞部位 通过对现有代理进行化学修改而产生的漏洞 临床疗效，以及新药的进一步设计和合成 基于生化和药理学原理，以及(C) 根据新陈代谢作用选择药物用于 联合使用，从而获得更高的治疗效果。研究 重点放在以下几个方面：(A)对苯二酚酰亚胺、对苯二酚、 含色酮和硝基的生物还原烷基化试剂 对缺氧细胞的优先细胞毒性；(B)α-(N)-杂环 甲醛缩氨基硫脲，以努力开发第二种 具有临床应用潜力的核糖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 肿瘤细胞获得抗药性的机制 6-硫代嘌呤；(D)生物化学机理的开发和研究 吡啶N-氧化物的芳磺酰肼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-硫代鸟嘌呤和 2-脱氧-D-葡萄糖；(F)糖胺多糖在黑色素瘤中的作用 转移和抗转移剂的发展；(G)研究 2‘-azido-2’-deoxy-beta-D-arabinofuranosyladenine的比较作用 和阿拉伯糖基腺嘌呤；以及(H)6-硫代鸟嘌呤和 某些蒽环类药物可诱导白血病细胞分化。

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.