SITE-SELECTIVE CAMP ANALOGS AS ANTINEOPLASTICS AND CHEMOPREVENTIVES

位点选择性cAMP类似物的使用极大地促进了我们对 CAMP在生长控制中的作用机制。人们发现， 位点选择性cAMP类似物可以作为新的生物制剂，能够 在广谱诱导生长抑制和分化 人类癌细胞系，包括癌症、肉瘤和白血病， 而不会产生细胞毒性。8-氯-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)。这是第一次 30多年来将cAMP类似物引入临床试验 夏令营研究。值得注意的是，这是第一次展示一个营地 类似物可在微摩尔浓度下诱导其生物效应-- CAMP的生理浓度，而不是毫摩尔 报道的cAMP类似物的药理或细胞毒性浓度 所有以前的文学作品。这一发现给出了一个批判性的评估 CAMP类似物抑制生长的效力取决于类似物 选择性地调节RI和RII调节亚基的能力 确切地说，cAMP依赖的蛋白激酶，下调RI与上调 调节RII导致恢复正常平衡 癌细胞中的这些cAMP转导蛋白。反义的使用 提供的策略和逆转录病毒载体介导的基因转移技术 直接证据表明两种异构体，RI和RLI调节亚基 CAMP依赖的蛋白激酶，在细胞生长和 差异化；RI是增长刺激性，而RI是增长- 抑制和分化诱导蛋白。由于RI表达式是 在化学或病毒致癌过程中，在人类癌细胞中增强 在原发人类肿瘤和多药耐药(MDR)癌症中 细胞与非多药耐药亲本细胞相反，它是癌症的靶点 诊断和治疗。8-氯-cAMP和RI反义寡核苷酸， 那些有效下调RI和上调RLL的公司，提供了新的 癌症的分化治疗和化学预防的方法。 8-氯-cAMP目前在几个研究所进行I期临床研究， Y.S.Cho-cho-chong作为顾问参与合作。

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 with up- regulation of RII 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 RI and RlI regulatory subunits of cAMP-dependent protein kinase, have opposite roles in cell growth and differentiation; RI being growth stimulatory while RI is a growth- inhibitory and differentiation-inducing protein. As RI 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 RI antisense oligodeoxynucleotide, those that effectively down-regulate RI and up-regulate Rll, provide new approaches toward differentiation therapy and chemoprevention of cancer. 8-Cl-cAMP is now in Phase I clinical studies at several Institutes where Y.S. Cho-Chung is collaborating as the consultant.