Fumagillin Treatment of Hepatocellular Carcinoma in Rats: an in Vivo Study of Antiangiogenesis

Overview

Journal World J Gastroenterol

Publisher Baishideng Publishing Group

Specialty Gastroenterology

Date 2005 Feb 1

PMID 15682466

Citations 5

Authors

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

Affiliations

Soon will be listed here.

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 x 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 (range2-3) 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.

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References

Iida A, Yamaguchi A, Hirose K . Telomerase activity in colorectal cancer and its relationship to bcl-2 expression. J Surg Oncol. 2000; 73(4):219-23. DOI: 10.1002/(sici)1096-9098(200004)73:4<219::aid-jso6>3.0.co;2-q. View

Zimmerman M, Selzman C, Harken A . Surgical implications of therapeutic angiogenesis. Surgery. 1999; 125(3):243-9. View

KENMOCHI K, Sugihara S, Kojiro M . Relationship of histologic grade of hepatocellular carcinoma (HCC) to tumor size, and demonstration of tumor cells of multiple different grades in single small HCC. Liver. 1987; 7(1):18-26. DOI: 10.1111/j.1600-0676.1987.tb00310.x. View

Kishimoto K, Fujimoto J, Takeuchi M, Yamamoto H, Ueki T, Okamoto E . Telomerase activity in hepatocellular carcinoma and adjacent liver tissues. J Surg Oncol. 1998; 69(3):119-24. DOI: 10.1002/(sici)1096-9098(199811)69:3<119::aid-jso1>3.0.co;2-q. View

Wang J, Lou P, Henkin J . Selective inhibition of endothelial cell proliferation by fumagillin is not due to differential expression of methionine aminopeptidases. J Cell Biochem. 2000; 77(3):465-73. View

Ohmura Y, Aoe M, Andou A, Shimizu N . Telomerase activity and Bcl-2 expression in non-small cell lung cancer. Clin Cancer Res. 2000; 6(8):2980-7. View

Sin N, Meng L, Wang M, Wen J, Bornmann W, Crews C . The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. Proc Natl Acad Sci U S A. 1997; 94(12):6099-103. PMC: 21008. DOI: 10.1073/pnas.94.12.6099. View

Ohta K, Kanamaru T, Morita Y, Hayashi Y, Ito H, Yamamoto M . Telomerase activity in hepatocellular carcinoma as a predictor of postoperative recurrence. J Gastroenterol. 1998; 32(6):791-6. DOI: 10.1007/BF02936956. View

Hanahan D, Folkman J . Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996; 86(3):353-64. DOI: 10.1016/s0092-8674(00)80108-7. View

10.

Folkman J . Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995; 1(1):27-31. DOI: 10.1038/nm0195-27. View

11.

Isobe N, Uozumi T, Kurisu K, Kawamoto K . Antitumor effect of TNP-470 on glial tumors transplanted in rats. Anticancer Res. 1996; 16(1):71-6. View

12.

Shimada M, Hasegawa H, Gion T, Utsunomiya T, Shirabe K, Takenaka K . The role of telomerase activity in hepatocellular carcinoma. Am J Gastroenterol. 2000; 95(3):748-52. DOI: 10.1111/j.1572-0241.2000.01855.x. View

13.

Yamaoka M, Yamamoto T, Masaki T, Ikeyama S, Sudo K, Fujita T . Inhibition of tumor growth and metastasis of rodent tumors by the angiogenesis inhibitor O-(chloroacetyl-carbamoyl)fumagillol (TNP-470; AGM-1470). Cancer Res. 1993; 53(18):4262-7. View

14.

Prox D, Becker C, Pirie-Shepherd S, Celik I, Folkman J, Kisker O . Treatment of human pancreatic cancer in mice with angiogenic inhibitors. World J Surg. 2003; 27(4):405-11. DOI: 10.1007/s00268-002-6816-4. View

15.

Folkman J . Angiogenesis and apoptosis. Semin Cancer Biol. 2003; 13(2):159-67. DOI: 10.1016/s1044-579x(02)00133-5. View

16.

Konno H, Tanaka T, Matsuda I, Kanai T, Maruo Y, Nishino N . Comparison of the inhibitory effect of the angiogenesis inhibitor, TNP-470, and mitomycin C on the growth and liver metastasis of human colon cancer. Int J Cancer. 1995; 61(2):268-71. DOI: 10.1002/ijc.2910610221. View

17.

Ingber D, Fujita T, Kishimoto S, Sudo K, Kanamaru T, Brem H . Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature. 1990; 348(6301):555-7. DOI: 10.1038/348555a0. View

18.

Bradshaw R, Yi E . Methionine aminopeptidases and angiogenesis. Essays Biochem. 2002; 38:65-78. DOI: 10.1042/bse0380065. View

19.

Takahashi S, Kitamoto M, Takaishi H, Aikata H, Kawakami Y, Nakanishi T . Expression of telomerase component genes in hepatocellular carcinomas. Eur J Cancer. 2000; 36(4):496-502. DOI: 10.1016/s0959-8049(99)00284-1. View

20.

Folkman J . Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971; 285(21):1182-6. DOI: 10.1056/NEJM197111182852108. View