SITE-SELECTIVE CAMP ANALOGS AS ANTINEOPLASTICS AND CHEMOPREVENTIVES

作为抗肿瘤药和化学预防药的位点选择性 Camp 类似物

• 批准号: 3813329
• 负责人: Y S CHO-CHUNG
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3813329
• 关键词: antineoplastics; binding proteins; carcinogenesis inhibitor; cell differentiation; cell growth regulation; cellular oncology; chemical binding; cyclic AMP; cyclic AMP receptors; gene expression; genetic promoter element; isozymes; laboratory mouse; molecular oncology; mouse mammary tumor virus; neoplastic growth; nucleotide analog; oncogenes; protein kinase A; protooncogene; tissue /cell culture; tumor promoters

Cyclic AMP (cAMP) in mammalian cells functions by binding to cAMP receptor protein, the regulatory subunit of cAMP-dependent protein kinase. The cAMP receptor protein has two different cAMP binding sites, and cAMP analogs that selectively bind to either one of the two binding sites are known as Site 1-selective (C-2 and C-8 analogs) and Site 2-selective (C-6 analogs), respectively. Such site-selective cAMP analogs at micromolar concentrations exerted potent growth inhibition, with no sign of toxic effects, in a spectrum of human cancer cell lines, including those that are resistant to previously tested cAMP analogs, leukemia lines, v-ras-H oncogene-transformed NIH/3T3 cells, and v-ras(Ki) oncogene-or TGFalpha-transformed normal rat kidney (NRK) cells; the combination of a C-8 with a C-6 analog showed synergistic effects. The growth inhibition was not due to a block in a specific phase of cell cycle but paralleled selective modulation of type I versus type II protein kinase isozymes, suppression of cellular protooncogene expression, inhibition of TGFalpha production, phenotypic change, and differentiation (leukemic cells). It is suggested that the site-selective cAMP analogs, substituting for endogenous cAMP and binding to protein kinase, suppress the cancer cell growth not via directly inhibiting cell division but rather by promoting cell differentiation. Site-selective cAMP analogs thus provide new biological tools for investigating cell proliferation and differentiation and also for the improved management of human cancer. 8-C1-cAMP is now in preclinical phase I studies at the National Cancer Institute. A U.S. patent for the cAMP analogs, entitled "Derivatives of cyclic AMP as treatment for cancer," was applied for on May 25, 1988.

哺乳动物细胞中的cAMP(CAMP)通过与cAMP受体结合发挥作用 蛋白质，cAMP依赖的蛋白激酶的调节亚单位。营地 受体蛋白有两个不同的cAMP结合部位，cAMP类似物 选择性地与两个结合位点中的任何一个结合的称为 位点1选择性(C-2和C-8类似物)和位点2选择性(C-6类似物)， 分别进行了分析。这种微摩尔浓度的位置选择性cAMP类似物 具有很强的生长抑制作用，没有毒性影响的迹象 人类癌细胞系的光谱，包括那些对 之前测试的cAMP类似物，白血病株，v-ras-H 癌基因转化的NIH/3T3细胞和v-ras(Ki)癌基因-OR 转化的正常大鼠肾(NRK)细胞； C-8与C-6类似物表现出协同作用。生长抑制率为 不是由于细胞周期的某一特定时相受阻，而是平行的 I型与II型蛋白激酶同工酶的选择性调节， 抑制细胞原癌基因表达，抑制肿瘤生长因子α 产生、表型变化和分化(白血病细胞)。它是 建议用部位选择性cAMP类似物，替代内源性 CAMP和蛋白激酶结合抑制癌细胞生长不是通过 直接抑制细胞分裂，而是通过促进细胞 差异化。因此，位点选择性cAMP类似物提供了新的生物学 研究细胞增殖和分化的工具，以及 改善对人类癌症的管理。 8-c1-cAMP目前正处于国家癌症研究所的临床前I期研究 研究所。CAMP类似物的美国专利，题为“衍生的 用于癌症治疗的环磷酰胺“于1988年5月25日申请。