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.

现场选择营地类似物的使用大大推进了我们 了解在成长控制中营地作用机制。 它 被发现现场选择性营地类似物可以充当新颖 能够诱导生长抑制和的生物学剂 在广泛的人类癌细胞系中的分化， 包括癌，肉瘤和白血病，而不会引起 细胞毒性。 8-CL训练营，最有效的现场选择营地类似物， 被选为临床前I期抗塑料 国家癌症研究所（1988年1月27日）。 这是第一个 将营地模拟引入30多年的临床测试中 营地研究。 值得注意的是，这是第一次演示 营地类似物可以在微摩尔诱导其生物学作用 浓度 - 营地的生理浓度，而不是 cAMP的毫摩尔药理或细胞毒性浓度 类似物在所有以前的文献中报道。 该发现渲染了 批判性评估营地类似物的效力 抑制取决于模拟选择性调节的能力 cAMP依赖性蛋白激酶的RI和RII调节亚基 确切地说，Ri alpha的下调，并上调了Riibeta 导致恢复这些营地的正常平衡 在癌细胞中转导蛋白质。 反义策略的使用 提供的逆转录病毒介导的基因转移技术提供了 直接证据表明两种同工型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 生长与分化； rialpha是生长刺激性的 riibeta是一种抑制生长的诱导蛋白。 由于化学或病毒期间rialpha的表达得到增强 癌变，在人类癌细胞系中，在原发性人类肿瘤中， 在多药耐药（MDR）癌细胞中与非MDR 亲本细胞，它是癌症诊断和治疗的靶标。 8- Cl-camp和rialpha反义寡脱氧核苷酸，那些 有效地下调RI和上调Riibeta提供了新的 分化治疗和化学预防的方法 癌症。 现在已经完成了8-CL-cAMP的I期临床研究。