Hu J J, Luke A, Chellani M, Zirvi K A, Lea M A
Department of Biochemistry, UMDNJ-New Jersey Medical School, Newark 07103.
Biochem Pharmacol. 1988 Jun 1;37(11):2259-66. doi: 10.1016/0006-2952(88)90590-4.
In past work, the selective effects of sodium cyanate on macromolecular synthesis in tumors have not been seen with cells in culture. We have explored the possibility that differences in the response of tumor cells to cyanate in vivo and in vitro may be related to the pH in the environment to which cells are exposed. When rat hepatoma (HTC) cells were incubated with sodium cyanate (0.25 mg/ml), there was a greater inhibition of precursor incorporation into RNA and DNA with a decrease in pH from 7.4 to 6.6. At pH 7.4 there was no significant effect of sodium cyanate on the incorporation of [3H]leucine into protein of rat hepatocytes and HTC cells, but at pH 6.6 there were decreases of 50% or greater. The time of response and the reversibility of the inhibitory effects of sodium cyanate were not those anticipated from carbamoylation of amino groups but were compatible with modification of sulfhydryl groups. The uptake of [14C]sodium cyanate in HTC cells and human colon cancer (HT29) cells was greater at pH 6.6 than at 7.4. Over a period of 4 days there was a slower rate of cell division by HTC and HT29 at pH 6.6 than at pH 7.4. The addition of sodium cyanate caused a further reduction in the rate of proliferation, and at a concentration of 0.25 mg sodium cyanate/ml there were decreases in cell numbers. The data suggested that a lower interstitial pH in tumors than normal tissues would result in greater sensitivity to inhibitory effects of sodium cyanate on macromolecular synthesis.
在以往的研究中，氰酸钠对肿瘤中大分子合成的选择性作用在培养细胞中并未观察到。我们探讨了肿瘤细胞在体内和体外对氰酸盐反应存在差异可能与细胞所处环境的pH值有关的可能性。当大鼠肝癌（HTC）细胞与氰酸钠（0.25 mg/ml）一起孵育时，随着pH值从7.4降至6.6，前体掺入RNA和DNA的抑制作用增强。在pH 7.4时，氰酸钠对大鼠肝细胞和HTC细胞中[3H]亮氨酸掺入蛋白质没有显著影响，但在pH 6.6时，掺入量减少了50%或更多。氰酸钠抑制作用的反应时间和可逆性并非氨基甲酰化所预期的那样，而是与巯基的修饰相符。[14C]氰酸钠在HTC细胞和人结肠癌（HT29）细胞中的摄取在pH 6.6时比在pH 7.4时更高。在4天的时间里，HTC和HT29细胞在pH 6.6时的细胞分裂速度比在pH 7.4时慢。添加氰酸钠导致增殖速度进一步降低，在氰酸钠浓度为0.25 mg/ml时，细胞数量减少。数据表明，肿瘤组织中的间质pH值低于正常组织会导致对氰酸钠对大分子合成抑制作用的敏感性更高。
