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: 5200922
• 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/5200922
• 关键词: Retroviridae; antineoplastics; antisense nucleic acid; cancer prevention; carcinogenesis inhibitor; cell differentiation; cell growth regulation; chemical carcinogenesis; chemoprevention; cyclic AMP; drug screening /evaluation; gene expression; growth inhibitors; isozymes; multidrug resistance; neoplasm /cancer chemotherapy; neoplastic cell; nucleotide analog; oligonucleotides; protein kinase A; tissue /cell culture; transfection /expression vector; viral carcinogenesis

The use of site-selective cAMP analogs greatly advanced our understanding of the mechanism of cAMP action in growth control. It was discovered that site-selective cAMP analogs can act as novel biological agents capable of inducing growth inhibition and differentiation in a broad spectrum of human cancer cell lines, including carcinomas, sarcomas, and leukemias, without causing cytotoxicity. 8-Cl-cAMP, the most potent site-selective cAMP analog, was selected as a preclinical Phase I antineoplastic agent of the National Cancer Institute (January 27, 1988). It was the first introduction of a cAMP analog into clinical testing in over 30 years of cAMP research. Significantly, this was the first demonstration that a cAMP analog can induce its biological effect at micromolar concentrations-the physiological concentration of cAMP, as opposed to the millimolar pharmacological or cytotoxic concentrations of cAMP analogs reported in all previous literature. The discovery rendered a critical assessment that the potency of a cAMP analog in growth inhibition depends on the analog's ability to selectively modulate the RI and RII regulatory subunits of cAMP-dependent protein kinase precisely, down-regulation of RI alpha with up-regulation of RIIbeta leading to the restoration of the normal balance of these cAMP transducing proteins in cancer cells. The use of antisense strategy and retroviral vector-mediated gene transfer technology provided direct evidence that two isoforms, the RIalpha and RIIbeta regulatory subunits of cAMP-dependent protein kinase, have opposite roles in cell growth and differentiation; RIalpha being growth stimulatory while RIIbeta is a growth-inhibitory and differentiation-inducing protein. As RIalpha expression is enhanced during chemical or viral carcinogenesis, in human cancer cell lines, in primary human tumors, and in multidrug-resistant (MDR) cancer cells as opposed to non-MDR parental cells, it is a target for cancer diagnosis and therapy. 8- Cl-cAMP and RIalpha antisense oligodeoxynucleotide, those that effectively down-regulate RI and up-regulate RIIbeta provide new approaches toward differentiation therapy and chemoprevention of cancer. A Phase I clinical study of 8-Cl-cAMP has now been completed.

位点选择性 cAMP 类似物的使用极大地推进了我们的研究 了解 cAMP 在生长控制中的作用机制。 它 发现位点选择性 cAMP 类似物可以充当新颖的 能够诱导生长抑制的生物制剂 广泛的人类癌细胞系的分化， 包括癌、肉瘤和白血病，但不会引起 细胞毒性。 8-Cl-cAMP，最有效的位点选择性 cAMP 类似物， 被选为临床前I期抗肿瘤药物 国家癌症研究所（1988 年 1 月 27 日）。 这是第一个 30 多年来将 cAMP 类似物引入临床测试 cAMP 研究。 值得注意的是，这是第一次演示 cAMP类似物可以在微摩尔浓度下诱导其生物效应 浓度-cAMP 的生理浓度，与 cAMP 的毫摩尔药理学或细胞毒性浓度 以前所有文献中报道的类似物。 这一发现提出了 cAMP 类似物在生长中的效力的严格评估 抑制取决于类似物选择性调节的能力 cAMP 依赖性蛋白激酶的 RI 和 RII 调节亚基 确切地说，RI α 的下调和 RIIbeta 的上调 导致这些cAMP恢复正常平衡 在癌细胞中转导蛋白质。 反义策略的运用 并提供逆转录病毒载体介导的基因转移技术 直接证据表明两种亚型，RIalpha 和 RIIbeta 调节 cAMP依赖性蛋白激酶的亚基，在细胞中具有相反的作用 生长和分化； RIalpha 具有生长刺激作用，同时 RIIbeta 是一种生长抑制和分化诱导蛋白。 由于 RIalpha 表达在化学或病毒过程中增强 致癌作用，在人类癌细胞系中，在原发性人类肿瘤中， 与非 MDR 癌细胞相比，在多重耐药 (MDR) 癌细胞中 亲代细胞，它是癌症诊断和治疗的靶点。 8- Cl-cAMP 和 RIalpha 反义寡脱氧核苷酸， 有效下调 RI 并上调 RIIbeta 提供新的 分化治疗和化学预防的方法 癌症。 8-Cl-cAMP的I期临床研究现已完成。