Basic Research
Copyright ©2005 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 14, 2005; 11(6): 771-777
Published online Feb 14, 2005. doi: 10.3748/wjg.v11.i6.771
Fumagillin treatment of hepatocellular carcinoma in rats: An in vivo study of antiangiogenesis
I-Shyan Sheen, Kuo-Shyang Jeng, Wen-Juei Jeng, Chi-Juei Jeng, Yi-Ching Wang, Shu-Ling Gu, Shin-Yun Tseng, Chien-Ming Chu, Chia-Hui Lin, Kuo-Ming Chang
I-Shyan Sheen, Liver Reserch Unit, Chang Gung Memorial Hospital, Taipei, Taiwan, China
Kuo-Shyang Jeng, Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan, China
Wen-Juei Jeng, National Yang-Ming University Medical College, Taipei, Taiwan, China
Chi-Juei Jeng, National Taiwan University Medical College, Taipei, Taiwan, China
Yi-Ching Wang, Shu-Ling Gu, Shin-Yun Tseng, Chien-Ming Chu, Chia-Hui Lin, Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan, China
Kuo-Ming Chang, Department of Pathology, Mackay Memorial Hospital, Taipei, Taiwan, China
Author contributions: All authors contributed equally to the work.
Supported by Grants From The New Century Health Care Promotion Foundation, Taiwan, and Professor Wen-Pin Lien
Correspondence to: Kuo-Shyang Jeng, M.D., F.A.C.S., Department of Surgery, Mackay Memorial Hospital, No.92, Sec2, Chung-san North Road, Taipei, Taiwan, China. issheen.jks@msa.hinet.net
Telephone: +886-2-5433535 Fax: +886-2-7065704
Received: June 8, 2004
Revised: June 10, 2004
Accepted: July 27, 2004
Published online: February 14, 2005
Abstract

AIM: To investigate the effect and possible mechanisms of antiangiogenesis therapy for HCC in rats.

METHODS: Adult male LEW/SsN rats were divided into 3 groups, 25 animals each. Group A was the control group. Groups B and C were given diethylnitrosamine, 5 mg/kg/d. In addition, group C rats received an intraperitoneal injection of fumagillin, 30 mg/(kg·d). Five animals in each group were killed at 6th, 12th, 18th, 20th and 24th wk to evaluate the development of HCC and metastasis. Weight of the rats, liver tumors, and number of organs involved by HCC were measured at each stage. We compared methionine aminopeptidase-2 (MetAP-2) mRNA, Bcl-2 mRNA, telomerase mRNA, and telomerase activity at 24th wk in the liver tissue of group A rats and tumor tissue of HCC from group B and C rats.

RESULTS: No HCC developed in group A, but tumors were present in group B and C rats by the 18th wk. At wk 20 and 24, the median liver weight in group B was 0.64 g (range: 0.58-0.70 g) and 0.79 g (range: 0.70-0.90 g) (P = 0.04), and that in group C was 0.37 g (range: 0.35-0.42 g) and 0.39 g (range: 0.35-0.47 g) (P = 0.67). The liver weight in group C rats was significantly lower than that in group B rats (P = 0.009). At the same time, the median metastasis score (number of organ systems involved) was 3 (range 2-3) in group B, and 1 (range 1-2) in group C, a significant difference between the groups (P = 0.007, 0.004). The levels of MetAP-2 mRNA were significantly higher in groups B and C than in group A (P = 0.025), and significantly higher in group C than in group B (P = 0.047). The level of Bcl-2 mRNA was significantly higher in group B than in group A (P = 0.024), but lower in group C than in group B, although not significantly (P = 0.072). Telomerase mRNA was significantly higher in group B than in group A (P = 0.025), but significantly lower in group C than in group B (P = 0.016). The same inter-group relationship was also true for telomerase activity (P = 0.025 and 0.046).

CONCLUSION: Fumagillin effectively inhibits both liver tumor growth and metastasis in rats in vivo. A possible mechanism is fumagillin-induced inhibition of MetAP-2, which plays an essential role in endothelial cell proliferation. Inhibition of MetAP-2 also results in inhibition of Bcl-2 and telomerase activity.

Keywords: Hepatocellular carcinoma, Antiangiogenesis therapy, Fumagillin, MetAP-2