Prevention of hepatic carcinogenesis and treatment of hepatoma by way of inhibition of the activation of Ras oncogene

HMG-CoA还原酶抑制剂通过抑制甲磺酸途径，调节Ras蛋白的功能。我们试图证明它们能够抑制肝细胞和某些肝癌细胞系的生长，并对肝细胞癌有可能的治疗作用。辛伐他汀对肝癌细胞株(Hep G2、Hh-7、HLE、PLC/PRF/5)的生长抑制作用呈剂量依赖关系。结果：1.不同细胞系对细胞生长的抑制程度最为相似。普伐他汀对所有细胞株的生长均无抑制作用。由于肝癌细胞系不存在将普伐他汀转运到细胞内的阴离子转运系统，普伐他汀不能抑制这些细胞的生长。在足够量的外源性甲伐他酸存在下，辛伐他汀对肝癌细胞生长的抑制作用几乎被阻止。因此，很明显，这些细胞系的生长需要梅瓦隆途径。但法尼醇和异戊烯基腺嘌呤均不能阻止辛伐他汀对这些细胞系生长的抑制作用。肝细胞癌患者应用HMG-CoA还原酶抑制剂的临床试验表明，辛伐他汀可能有治疗作用，而普伐他汀则没有作用。

HMG-CoA reductase inhibiters inhibit the mevalonic pathway and then regulate the function of Ras protein. We tried to exhibit that they were able to inhibit the growth of hepatocyte and some kinds of hepatoma cell lines and that they had the possible therapeutic effect on hepatocellular carcinoma.1. Simvastasin inhibited the growth of hepatoma cell lines (Hep G2, HuH-7, HLE, PLC/PRF/5) as a dose dependent manner. The extents of inhibition of growth were all most same among these cell lines.2. Pravastatin did not have inhibitory effects of growth of all these cell lines. Since hepatoma cell lines did not have anion transporter system to transfer pravastatin into cells, pravastatin failed to inhibit the growth of these cells.3. The inhibitory effect of simvastatin on hepatoma cell growth was nearly prevented in the presence of sufficient amount of exogenous mevalonic acid. So it was obvious that the mevalonic pathway was required for the growth of these cell lines. But neither farnesol nor isopentenyl adenine prevented the simvastatin induced inhibition of the growth of these cell lines.4. Clinical trial of HMG-CoA reductase inhibiter administrated to patients with hepatocellular carcinoma revealed that simvastatin possibly had a therapeutic effects but pravastatin did not have.