Therapeutic efficacy of Traditional Chinese Medicine 319 recipe on hepatic fibrosis induced by carbon tetrachloride in rats.

BACKGROUND/AIMS: Hepatic fibrosis is a consequence of severe liver damage that occurs in many patients with chronic liver diseases. TCM 319 recipe is a Chinese Medicine formula which consists of six Chinese herbs. In this study, we investigated the anti-fibrotic efficacy and mechanisms of TCM 319 recipe. METHODS: Hepatic fibrosis in rats was induced by carbon tetrachloride (CCl4). 34 male adult SD rats were allocated into five groups (group 1-concomitant CCl4 and TCM 319 recipe for 8 weeks; group 2-CCl4 for 4 weeks and then CCl4 and TCM 319 recipe for 4 weeks; group 3-CCl4 alone for 8 weeks; group 4-TCM 319 recipe only for 8 weeks; group 5-untreated controls). After 8 weeks of treatment, serum ALT assay, liver tissue histological examination and immunostaining were carried out to examine the liver function and fibrosis degree. The expression levels of platelet derived growth factor (PDGF-B), PDGF-Rbeta, and transforming growth factor-beta 1 (TGF-beta1) were measured by quantitative RT-PCR and western blot. RESULTS: TCM 319 recipe reduced liver injury and attenuated hepatic fibrosis in group 1 compared with that in group 3. TCM 319 recipe suppressed the mRNA expression of tissue inhibitor of metalloproteinase 1 (TIMP-1). In addition, treatment with TCM 319 recipe significantly down-regulated mRNA expression of PDGF-B and PDGF-Rbeta, and it also suppressed protein expression of PDGF-Rbeta and TGF-beta1. CONCLUSIONS: TCM 319 recipe extracts could attenuate hepatic fibrosis induced by CCl4 in rats. The anti-fibrotic effect of TCM 319 recipe is associated with the down-regulation of mRNA expression of TIMP-1, PDGF-B and PDGF-Rbeta, and with the suppression of protein expression of PDGF-Rbeta and TGF-beta1.

Recombinant human arginase inhibits proliferation of human hepatocellular carcinoma by inducing cell cycle arrest.

Human hepatocellular carcinoma (HCC) has an elevated requirement for arginine in vitro, and pegylated recombinant human arginase I (rhArg-PEG), an arginine-depleting enzyme, can inhibit the growth of arginine-dependent tumors. While supplementation of the culture medium with ornithine failed to rescue Hep3B cells from growth inhibition induced by rhArg-PEG, citrulline successfully restored cell growth. The data support the roles previously proposed for ornithine transcarbamylase (OTC) in the arginine auxotrophy and rhArg-PEG sensitivity of HCC cells. Expression profiling of argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and OTC in 40 HCC tumor biopsy specimens predicted that 16 of the patients would be rhArg-sensitive, compared with 5 who would be sensitive to arginine deiminase (ADI), another arginine-depleting enzyme with anti-tumor activity. Furthermore, rhArg-PEG-mediated deprivation of arginine from the culture medium of different HCC cell lines produced cell cycle arrests at the G(2)/M or S phase, possibly mediated by transcriptional modulation of cyclins and/or cyclin dependent kinases (CDKs). Based on these results, together with further validation of the in vivo efficacy of rhArg-PEG against HCC, we propose that the application of rhArg-PEG alone or in combination with existing chemotherapeutic drugs may represent a specific and effective therapeutic strategy against HCC.

Long-term oral branched chain amino acids in patients undergoing chemoembolization for hepatocellular carcinoma: a randomized trial.

BACKGROUND: Patients undergoing transarterial chemoembolization for hepatocellular carcinoma have advanced tumour or severe cirrhosis and frequently have associated protein-calorie malnutrition. The role of nutritional supplements for such patients is unclear. AIM: To investigate, in a randomized controlled trial, any benefit of the long-term administration of branched chain amino acids in patients undergoing chemoembolization for hepatocellular carcinoma. METHODS: Forty-one patients received oral branched chain amino acids for up to four courses of chemoembolization and 43 patients did not receive any nutritional supplement. Morbidity, liver function, nutritional status, quality of life and long-term survival were compared between the two groups. RESULTS: The administration of branched chain amino acids resulted in a lower morbidity rate compared with the control group (17.1% vs. 37.2%, P = 0.039). In particular, the group given branched chain amino acids showed a significantly lower rate of ascites (7.3% vs. 23.2%, P = 0.043) and peripheral oedema (9.8% vs. 27.9%, P = 0.034). Significantly higher serum albumin, lower bilirubin and a better quality of life were observed after chemoembolization in the group given branched chain amino acids. However, there was no significant difference in survival between the two groups. CONCLUSIONS: Nutritional supplementation with oral branched chain amino acids is beneficial in increasing the serum albumin level, reducing the morbidity and improving the quality of life in patients undergoing chemoembolization for inoperable hepatocellular carcinoma.

Factors predictive of 5-year survival after transarterial chemoembolization for inoperable hepatocellular carcinoma.

BACKGROUND: Transarterial chemoembolization (TACE) is widely used for unresectable hepatocellular carcinoma (HCC), but the long-term survival benefit remains unclear. METHODS: Pretreatment variables were analysed for factors predictive of actual 5-year survival from a prospective database of patients with inoperable HCC treated by TACE between 1989 and 1996. RESULTS: Complete 5-year follow-up (median 91 months) was obtained for 320 patients who underwent a median of 4 (range 1-41) TACEs. Median tumour size was 9 (range 1-28) cm. There were 25 5-year survivors (8 per cent), including eight with tumours larger than 10 cm in diameter and three with portal vein branch involvement. On univariate analysis, female gender (P = 0.037), absence of ascites (P = 0.028), platelet count below 150 x10(9) per litre (P = 0.011), albumin concentration greater than 35 g/l (P = 0.04), alpha-fetoprotein level below 1000 ng/ml (P = 0.007), unilobar tumour (P = 0.027), fewer than three tumours (P = 0.015), absence of venous invasion (P = 0.011), and tumour diameter less than 8 cm (P = 0.021) were significant predictors of 5-year survival. Albumin concentration greater than 35 g/l (P = 0.011), unilobar tumour (P = 0.012) and alpha-fetoprotein level below 1000 ng/ml (P = 0.014) were independent prognostic factors on multivariate analysis. CONCLUSION: Five-year survival is possible with TACE for inoperable HCC, even in some patients with advanced tumours. Unilobar tumours, alpha-fetoprotein level below 1000 ng/ml and albumin concentration greater than 35 g/l were factors predictive of 5-year survival.