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 patients with advanced HCC, this randomized controlled trial was conducted between February 1990 and February 1998 at Osaka University Hospital. 91 consecutive patients <71 years old (mean age 62) with unresectable HCC were enroled in this study. 8 patients were withdrawn because of progressive liver dysfunction; 83 patients were randomized to standard treatment with or without pravastatin. All patients underwent transcatheter arterial embolization (TAE) followed by oral 5-FU 200 mg -1 d for 2 months. Patients were then randomly assigned to control (n = 42) and pravastatin (n = 41) groups. Pravastatin was administered at a daily dose of 40 mg. The effect of pravastatin on tumour growth was assessed by ultrasonography. Primary endpoint was death due to progression of HCC. The duration of pravastatin administration was 16.5 ± 9.8 months (mean ± SD). No patients in either group were lost to follow-up. Median survival was 18 months in the pravastatin group versus 9 months in controls (P = 0.006). The Cox proportional hazards model showed that pravastatin was a significant factor contributing to survival. Pravastatin prolonged the survival of patients with advanced HCC, suggesting its value for adjuvant treatment.

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So far, treatment with anti-cancer agents has failed to achieve satisfactory results in hepatocellular carcinoma. In the process of hepatocarcinogenesis, ras has been shown to play a role. ras requires a farnesyl moiety for activation. It has been found that UCFI-C (manumycin), an antibiotic, inhibits farnesyl protein transferase, an enzyme that catalyzes farnesylation. Therefore, we investigated the effects of UCFI-C on cell growth, prenylation of cellular proteins including ras and Rapl, MAP kinase activity, activities of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and synthesis of cholesterol in a ras-activated human hepatoma cell line, Hep G2. Treatment with varying concentrations of UCF1-C(10-30 microM for 24 and 72 hr resulted in a time- and dose-dependent inhibition of cell numbers. 3H-Thymidine incorporation was also inhibited in a dose-dependent manner, with 50% inhibition after 44 hr being observed at a concentration of 17 microM. UCFI-C dose-dependently inhibited ras farnesylation and MAP kinase activity, but did not decrease Rap 1++ geranylgeranylation or prenylation of 21-to 26-kDa proteins. Neither the activities of 3-hydroxy-3-methylglutaryl-coenzyme A reductase nor cholesterol synthesis were inhibited. These results suggest that UCFI-C antagonizes the growth of Hep G2 via the suppression of ras farnesylation and could be a lead for the development of new anti-cancer agents blocking the function of oncogenic ras associated with human cancer, including hepatocellular carcinoma.

Summary Modulation of cell growth by a combination of pravastatin [a 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitor] and d-limonene (an inhibitor of protein isoprenylation) was studied using Hep G2, a human hepatoma-derived cell line. Pravastatin, at 0.1 mm, produced 85% inhibition of cholesterol biosynthesis in Hep G2 cells. The combination of 0.1 mm pravastatin and 1.0 mm d-limonene had no further effect on the reduction seen with pravastatin alone. Addition of 0.1 mM pravastatin or 1.0 mM d-limonene did not significantly suppress DNA synthesis by the cells, whereas the combination suppressed it to 50% of the control level. Production of m-p2lras was markedly decreased to 35% of the control level by the combination of these two inhibitors. Both the reduction by pravastatin of farnesylpyrophosphate as substrate for protein:farnesyl transferase and inhibition of protein farnesylation by d-limonene seem to be responsible for the profound suppression of m-p21ras formation in the cells. However, dolichol synthesis was not suppressed by the combination of these inhibitors. In human fibroblasts, the combination suppressed m-p2lras production but not DNA synthesis. These findings suggest that the combination of pravastatin and d-limonene acts on cancer cell growth through inhibition of the post-translational processing of cellular proteins including p2lras, rather than through the suppression of cholesterol and dolichol biosynthesis. Thus, the combination of an HMG-CoA reductase inhibitor and an inhibitor of protein isoprenylation offers potential as a new approach for cancer therapy. (Kandutsch & Chen, 1977;Chen, 1981). In addition to serving as a precursor of the structural cholesterol required for cell proliferation, the mevalonic acid produced by HMG-CoA reductase seems to regulate cell growth independent of cholesterogenesis by playing a direct role in DNA synthesis (Quesney-Huneeus et al., 1979 Wolda & Glomset, 1988;Casey et al., 1989;Hancock et al, 1989;Schafer et al., 1989;Goldstein & Brown, 1990 Habenicht et al., 1980;Fairbanks et al., 1984;Maltese, 1984) as well as in vivo (Maltese et al., 1985). There seem to be three mechanisms that contribute to the effect of HMG-CoA reductase inhibitors on cell growth: (1) a decrease in the cellular cholesterol content owing to inhibition of cholesterol biosynthesis, (2) a reduction of the levels of dolichols and ubiquinones and (3) inhibition of the isoprenylation processing of cellular proteins including Ras proteins.Limonene, the predominant monoterpene in orange peel oil, has substantial chemopreventive and therapeutic effects against chemically induced cancers in rodents (Elegbede et al., 1984;Wattenberg & Coccia, 1991;Crowell, 1992 (Richards et al., 1990). The cholesterol metabolism of this cell line has already been studied in detail (Knowles et al., 1980;Wu et al., 1984;Hoeg et al., 1985;Erickson & Fielding, 1986). Thus, the Hep G2 cell line appears to be a good candidate for testing the growth-inhibitory effect of an HMG-CoA reductase inhibi...