CYCLIC AMP (CAMP) IN GROWTH CONTROL OF NEOPLASIA

哺乳动物细胞中的cAMP(CAMP)通过与cAMP结合发挥作用 受体蛋白，cAMP依赖蛋白的调节亚单位 激活剂。CAMP受体蛋白有两种不同的cAMP结合 和cAMP类似物选择性地与其中一个结合 两个结合位点称为L选择性结合位点(C-2和C-8 类似物)和2位选择性(0-6个类似物)。是这样的 微摩尔浓度的位置选择性cAMP类似物 有效的生长抑制作用，没有毒性影响的迹象 人类癌细胞系的光谱，包括那些 对先前测试的cAMP类似物、白血病株和 V-rash癌基因转化的NIH/3T3细胞； 8与C-6类似物表现出协同作用。增长 抑制作用不是由于细胞周期某一特定时相的阻断 但I型与II型的并行选择性调制 蛋白激酶同工酶与细胞原癌基因抑制 表达、表型变化和分化(白血病 单元格)。有人认为，选择性营地类似物， 取代内源性cAMP并与蛋白激酶结合， 抑制癌细胞生长不是通过直接抑制细胞 而是通过促进细胞分化来实现的。站点- 因此，选择性cAMP类似物提供了新的生物学工具 研究细胞的增殖和分化，以及 改善对人类癌症的管理。

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 l-selective (C-2 and C-8 analogs) and Site 2-selective (0-6 analogs), respectively. Such site selective cAMP analogs at micromolar concentrations exert potent growth inhibition with no sign of toxic effects in a spectrum of human cancer cell lines, including those that are resistant to cAMP analogs tested previously, leukemia lines, and v-rasH oncogene-transformed NIH/3T3 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 proto-oncogene expression, 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.