Katsaros D, Ally S, Cho-Chung Y S
Cellular Biochemistry Section, National Cancer Institute, Bethesda, MD 20892.
Int J Cancer. 1988 Jun 15;41(6):863-7. doi: 10.1002/ijc.2910410616.
Cyclic AMP (cAMP) analogues that selectively bind to either one of the two binding sites of cAMP-dependent protein kinase demonstrate a potent inhibition of the growth stimulated by estrogen in MCF-7 human breast-cancer cells in culture. The site-selective analogues, which are more potent activators of protein kinase than the analogues studied earlier, exhibit growth inhibition at micromolar concentrations. Among the analogues tested, 8-Cl-cAMP (Site I-selective) and N6-benzyl-cAMP (Site 2-selective) are the 2 most potent inhibitors, causing 40-70% inhibition of the estrogen-stimulated growth at 10-20 microM concentrations with no sign of toxicity. 8-Cl-cAMP (1 microM) in combination with N6-benzyl-cAMP (0.5 microM) almost completely blocks estrogen-stimulated growth, demonstrating synergism between the Site 1- and Site 2-selective analogues. The growth inhibition parallels an increase in the R11 cAMP receptor protein with a decrease in the R1 receptor as well as reduction of c-myc and c-ras oncoproteins, whereas growth inhibition by tamoxifen does not affect the levels of the cAMP receptor proteins or the c-myc and c-ras protein levels. Site-selective cAMP analogues are antagonistic to estrogen stimulation of breast-cancer cell growth through a mechanism different from that of tamoxifen.
能选择性结合环磷酸腺苷（cAMP）依赖性蛋白激酶两个结合位点之一的cAMP类似物，在体外培养的MCF-7人乳腺癌细胞中，对雌激素刺激的生长具有强效抑制作用。这些位点选择性类似物作为蛋白激酶的激活剂，比早期研究的类似物更有效，在微摩尔浓度下即可表现出生长抑制作用。在所测试的类似物中，8-氯-cAMP（位点I选择性）和N6-苄基-cAMP（位点2选择性）是两种最有效的抑制剂，在10-20微摩尔浓度下可导致雌激素刺激的生长受到40-70%的抑制，且无毒性迹象。8-氯-cAMP（1微摩尔）与N6-苄基-cAMP（0.5微摩尔）联合使用几乎可完全阻断雌激素刺激的生长，表明位点1选择性和位点2选择性类似物之间存在协同作用。生长抑制与R11 cAMP受体蛋白增加、R1受体减少以及c-myc和c-ras癌蛋白减少平行，而他莫昔芬引起的生长抑制并不影响cAMP受体蛋白水平或c-myc和c-ras蛋白水平。位点选择性cAMP类似物通过一种不同于他莫昔芬的机制拮抗雌激素对乳腺癌细胞生长的刺激作用。
