Circumvention of cisplatin resistance in human ovarian carcinoma cells by modulation of cellular protein kinase C acitivity

基于12-0-十四酰基佛波醇-13-乙酸酯（TPA）激活蛋白激酶C（PKC）增强人卵巢癌细胞系2008的顺式二氨二氯铂（II）（DDP）敏感性的报道（Isonishi等人），我们已经研究了这种致敏效应的细胞机制，并试图在体内实验中扩展这种效应。发现TPA激活PKC可增强2008细胞对DDP、卡铂（CBDCA）和（乙醇酸-o，o '）二氨铂（II）（254-S）的敏感性。TPA能够将DDP抗性2008/C13*5.25亚系对三种药物中的每一种的敏感性增强到与2008细胞相同的程度。TPA对[^3H]-cis-dichloroethylenediamine-platinum（II）[^3H]-DEP）或CBDCA的摄取无显著影响，对谷胱甘肽含量无显著影响，对金属硫蛋白IIA mRNA水平无显著影响，但对DWA 2114 R、（-）-（R）-2-aminomethylpyrrolidone（2-aminomethylpyrrolidone）、（-）-（R）-2-aminomethylpyrrolidone（2-aminomethylpyrrolidone）、（-）-（R）-2-aminomethylpyrrolidone（2-aminomethylpyrrolidone）、（-）-（R）-2-aminomethylpyrrolidone（2-aminomethylpyrrolidone）、（-）-（R）-2-aminomethylpyrrolidone（2-aminomethylpyrrolidone ...更多信息 二（1，1-环丁烷二羧酸）-铂（II）一水合物，在2008细胞。此外，它确实使2008/C13*5.25细胞的DWA 2114 R抗性增加了1.7倍（p<0.05），而不是增加敏感性。在此基础上，我们研究了其它PKC激活剂TNF α对DDP抗裸鼠2008肿瘤作用的影响。单独TNF α（100 μ g）不能改变2008异种移植物的体内生长，也不能改变DDP诱导的全身毒性。低剂量DDP（7 mg/kg）可显著抑制肿瘤生长。TNF α和低剂量DDP的组合导致肿瘤生长进一步减少（p=0.0002），并产生显著更长的生存期（p=0.0071）。提示TNF α有可能增强DDP对卵巢癌的临床抗肿瘤作用，而不改变DDP的全身毒性。少

On the bases of the report that activation of protein kinase C (PKC) by 12-0-tetradecanoylphorbol-13-acetate (TPA) enhances the cis-Diamminedichloroplatinum (II) (DDP) sensitivity of the human ovarian carcinoma cell line 2008 (Isonishi et al.), we have investigated the cellular mechanism of this sensitization effect and have tried to extend this effect in vivo experiments. Activation of PKC by TPA was found to enhance the sensitivity of 2008 cells to DDP,carboplatin (CBDCA) and (Glycolato-o, o') diammineplatinum (II) (254-S). TPA was able to enhance the sensitivity of the DDP-resistant 2008/C13*5.25 subline to each of the three drugs to the same extent as for the 2008 cells. TPA produced no significant change in the uptake of [^3H]-cis-dichloro (ethylenediamine)-platinum (II) [^3H]-DEP) or CBDCA.It did not after glutathione content and induced rather than suppressed methallothionein IIA mRNA levels.In contrast, TPA did not alter the sensitivity to DWA2114R, (-)-(R)-2-aminomethylpyrroli … More dine (1,1-cyclobutanedicarboxylato)-platinum (II) monohydrate, in 2008 cells. Furthermore, it did render the DWA2114R-resistance of 2008/C13*5.25 cells by a factor of 1.7 fold (p<0.05) rather than increase sensitivity. This suggests that TPA sensitizatoin effect was not common to any platnium compounds but was strongly related to their ligands.Based upon these in vivo data, we have determined the effect of TNFalpha, one of the other PKC activators, on the sntitumor effect of DDP against 2008 tumor xenograft in nude mice. TNFalpha (100mug) alone did not alter the in vivo growth of 2008 xenograft not did it alter DDP induced systemic toxicity. Low dose DDP (7mg/kg) caused a statistically significant reduction in tumor growth. The combination of TNFalpha and low dose DDP resulted in further reduction in tumor growth (p=0.0002) and produced significantly longer survival (p=0.0071). This is strongly indicating that TNFalpha has the potential to enhance the clinical antitumor effect of DDP in patient with ovarian carcinoma without altering systemic toxicity of DDP. Less