Katsaros D, Tortora G, Tagliaferri P, Clair T, Ally S, Neckers L, Robins R K, Cho-Chung Y S
Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, MD 20892.
FEBS Lett. 1987 Oct 19;223(1):97-103. doi: 10.1016/0014-5793(87)80517-3.
Site-selective cyclic AMP analogs bind to site 1 or site 2 of the known cAMP-binding sites depending on the position of substituents on the purine ring, either at C-2 and C-8 (site 1) or at C-6 (site 2). The growth inhibitory effect of such site-selective cAMP analogs used in this investigation with 15 human cancer cell lines surpassed that of analogs previously tested. The most potent analogs were 8-chloro, N6-benzyl and N6-phenyl-8-p-chlorophenylthio-cAMP. The combination of a C-8 with an N6 analog had synergistic effects. The 24 site-selective analogs tested produced growth inhibition ranging from 30 to 80% at micromolar concentrations with no sign of toxic effects. Growth inhibition was not due to a block in a specific phase of the cell cycle but paralleled a change in cell morphology, an increase of the RII cAMP receptor protein and a decrease of p21 ras protein. Since the adenosine counterpart of the 8-chloro analog produced G1 synchronization without affecting the RII and p21 ras protein levels, it is unlikely that an adenosine metabolite is involved in the analog effect. Site-selective cAMP analogs thus provide a new biological tool for control of cancer growth.
位点选择性环磷酸腺苷（cAMP）类似物根据嘌呤环上取代基的位置，结合到已知cAMP结合位点的位点1或位点2，取代基位置要么在C-2和C-8（位点1），要么在C-6（位点2）。本研究中使用的此类位点选择性cAMP类似物对15种人类癌细胞系的生长抑制作用超过了先前测试的类似物。最有效的类似物是8-氯、N6-苄基和N6-苯基-8-对氯苯硫基-cAMP。C-8类似物与N6类似物联合使用具有协同作用。所测试的24种位点选择性类似物在微摩尔浓度下产生30%至80%的生长抑制，且无毒性作用迹象。生长抑制并非由于细胞周期特定阶段的阻滞，而是与细胞形态变化、RII cAMP受体蛋白增加和p21 ras蛋白减少平行。由于8-氯类似物的腺苷对应物产生G1期同步化而不影响RII和p21 ras蛋白水平，因此腺苷代谢产物不太可能参与类似物的作用。因此，位点选择性cAMP类似物为控制癌症生长提供了一种新的生物学工具。
