Hepatocellular Carcinoma (hcc) Causes Death in Patients with Cirrhosis and Is One of the Most Prevalent Malignant Tumours Effect of Pravastatin on Survival in Patients with Advanced Hepatocellular Carcinoma. a Randomized Controlled Trial
Hepatocellular Carcinoma (hcc) Causes Death in Patients with Cirrhosis and Is One of the Most Prevalent Malignant Tumours Effect of Pravastatin on Survival in Patients with Advanced Hepatocellular Carcinoma. a Randomized Controlled Trial
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S. Kawata;E. Yamasaki;T. Nagase;Y. Inui;N. Ito;Y. Matsuda;M. Inada;S. Tamura;S. Noda-S.-No
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作者：
S. Kawata;E. Yamasaki;T. Nagase;Y. Inui;N. Ito;Y. Matsuda;M. Inada;S. Tamura;S. Noda-S.-No
HCC的5年生存率很低，而且没有有效的化疗。信号转导抑制剂，包括法尼基转移酶抑制剂和丝裂原活化蛋白激酶（MAPK）激酶抑制剂，已被开发作为抗癌药物。3-羟基-3-甲基戊二酰辅酶A （HMG-CoA）还原酶的活性与哺乳动物细胞生长呈正相关，HMG-CoA是胆固醇生物合成的限速酶（Kandutsch和Chen， 1979）。Mevalonic acid由HMG-CoA还原酶产生，独立于胆固醇生成调节细胞生长：Ras p21和层蛋白A和B在羧基端被mevalonate衍生的法尼基类异戊二烯共价修饰（Goldstein和Brown， 1990）。当将HMG-CoA还原酶抑制剂添加到培养或体内的增殖细胞中时，可能作为信号转导抑制剂表现出细胞抑制活性（Goldstein等，1979；Habenicht等，1980；Maltese等，1985）。这些抑制剂减少法尼基类异戊二烯形成，可能通过干扰Ras p21的功能抑制肿瘤生长。然而，尚无关于此类抑制剂是否对癌症患者有潜在作用的报道。在本研究中，我们测试了HMG-CoA还原酶抑制剂是否有助于晚期HCC患者的生存。在一项随机对照试验中，我们对经导管动脉栓塞（TAE）后的肝癌患者给予普伐他汀（40 mg day -1） （Charnsagavej et al ., 1983; Yamada et al ., 1983; Stefanini et al ., 1995）和口服5-氟尿嘧啶（5-FU）作为标准治疗。该队列包括91例年龄小于70岁的不可切除晚期HCC患者（图1）；男性71例，女性20例。平均年龄62岁（39 - 70岁）。肝硬化的诊断局限于生化资料和超声检查（US）。47例患者经超声引导下肝活检诊断为潜在肝脏疾病。HCC的诊断是基于临床特征和超声、计算机断层扫描和肝动脉造影的结果。肿瘤分期（I - iv）根据日本原发性肝癌研究组的标准确定：I期，单个肿瘤最大尺寸≤2cm，无血管侵犯；II期：单个肿瘤最大尺寸< 2cm，伴血管侵犯，或多发肿瘤总结：化疗对肝细胞癌（HCC）无效。HMG-CoA还原酶抑制剂对癌细胞具有细胞抑制活性，但其临床用途尚不清楚。研究普伐他汀是否能延长HMG-CoA还原酶抑制剂的生存期。
HCC has a dismal 5-year survival rate, and there is no effective chemotherapy. Signal transduction inhibitors, including farnesyl transferase inhibitors and mitogen-activated protein kinase (MAPK) kinase inhibitors, have been developed as anti-cancer agents The activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of cholesterol biosynthesis, has been positively correlated with mammalian cell growth (Kandutsch and Chen, 1979). Mevalonic acid, produced by HMG-CoA reductase, regulates cell growth independent of cholesterogenesis: Ras p21 and lamins A and B undergo covalent modification at the carboxyl terminus by meval-onate-derived farnesyl isoprenoid (Goldstein and Brown, 1990). HMG-CoA reductase inhibitors exhibit cytostatic activity possibly as signal transduction inhibitors, when added to proliferating cells in culture or in vivo (Goldstein et al, 1979; Habenicht et al, 1980; Maltese et al, 1985). Decreased farnesyl isoprenoid formation by these inhibitors could lead to suppression of tumour growth by interfering with the function of Ras p21. However, there are no report on whether such inhibitors have potential in cancer patients. In this study, we tested whether administration of HMG-CoA reductase inhibitor would contribute to the survival of patients with advanced HCC. We administered pravastatin (40 mg day –1), for which the liver has a high affinity, to HCC patients in a randomized controlled trial after transcatheter arterial emboliza-tion (TAE) (Charnsagavej et al, 1983; Yamada et al, 1983; Stefanini et al, 1995) and oral 5-fluorouracil (5-FU) as standard treatment. Patients The cohort comprised 91 consecutive patients with unresectable advanced HCC who were younger than 70 years old (Figure 1); 71 patients were male and 20 were female. The mean age was 62 (ranging from 39 to 70). The diagnosis of cirrhosis was confined by biochemical data and ultrasonography (US). The histologic diagnosis of underlying liver disease was carried out in 47 patients by US-guided liver biopsy. The diagnosis of HCC was based on clinical features and findings from US, computed tomography, and hepatic arteriography. Tumour stage (I–IV) was determined according to the criteria of the Primary Liver Cancer Study Group of Japan: stage I, a single tumour ≤2 cm in its greatest dimension without vascular invasion; stage II, a single tumour <2 cm in its greatest dimension with vascular invasion, or multiple tumours Summary Chemotherapy is not effective for hepatocellular carcinoma (HCC). HMG-CoA redutase inhibitors have cytostatic activity for cancer cells, but their clinical usefulness is unknown. To investigate whether pravastatin, a potent HMG-CoA reductase inhibitor, prolongs survival in …