肿瘤致癌基因p21ras蛋白质的后转录翻译修饰需要一种脂质中间体法尼酰化，这是胆固醇生物合成中的一步，以便p21ras与细胞膜结合并使其能够转化培养细胞。我们测试了洛伐他汀（一种特异性胆固醇生物合成抑制剂）抑制体内ras致癌基因转化细胞生长的能力。从人类膀胱癌EJ转染H-ras致癌基因的Balb/c小鼠3T3细胞在裸鼠身上高度致瘤。转化EJ细胞的免疫共沉淀研究显示，洛伐他汀（1-100微摩尔）浓度依赖性地抑制p21ras与细胞膜的结合，并且10微摩尔的浓度可将p21ras与膜结合的数量降低50％。洛伐他汀在浓度范围内抑制EJ细胞生长，该范围与抑制p21ras与细胞膜结合所需范围密切相似。用洛伐他汀（50毫克/千克）处理皮下（s.c.）EJ肿瘤的裸鼠能够显著抑制这些肿瘤的生长，最早在四天时发现，到第12天时，洛伐他汀处理组的动物的肿瘤平均大小比盐水对照组小了3倍。 Western印迹研究表明，洛伐他汀（50毫克/千克）也能够抑制裸鼠身上植入的EJ肿瘤的p21ras与细胞膜结合。这些结果表明，洛伐他汀（一种胆固醇生物合成抑制剂）能够抑制经H-ras致癌基因转化的细胞在体内的肿瘤生长。结果还表明，抑制p21ras与细胞膜结合是ras致癌基因肿瘤转化的一个必要步骤，这是洛伐他汀发挥其抗肿瘤活性的一种机制。

Post-translational modification of oncogenic p21ras proteins with farnesyl, a lipid intermediate in cholesterol biosynthesis, is required for p21ras membrane association and for the ability of p21ras to transform cultured cells. We have tested the ability of lovastatin, a specific inhibitor of cholesterol biosynthesis, to inhibit the growth of ras oncogene-transformed cells in vivo. Balb/c mouse 3T3 cells, transfected with H-ras oncogene from human EJ bladder carcinoma, were highly tumorigenic in nude mice. Immunoprecipitation studies with transformed EJ cells showed that lovastatin (1-100 microM) inhibited p21ras membrane association in a concentration-dependent manner and that a 10 microM concentration reduced the amount of p21ras bound to the membrane by 50%. Lovastatin also inhibited EJ cell growth in a concentration range that closely paralleled that required for inhibition of p21ras membrane association. Treatment of nude mice bearing subcutaneous (s.c.) EJ tumors with lovastatin (50 mg/kg) significantly inhibited the abilities of these tumors to grow as early as four days and, by day 12, the lovastatin treated group of animals had tumors with an average size that was 3-fold smaller than those in the saline treated group. Western blotting studies showed that lovastatin (50 mg/kg) was also able to inhibit p21ras membrane association in EJ tumors implanted s.c. in nude mice. These results demonstrate that lovastatin, an inhibitor of cholesterol biosynthesis, inhibited in vivo tumor growth of H-ras oncogene transformed cells. The results also suggest that inhibition of p21ras membrane association, an essential step in ras oncogene neoplastic transformation, is one mechanism by which lovastatin may express its antitumor activity.