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Gene transfer of kringle 1-5 suppresses tumor development and improves prognosis of mice with hepatocellular carcinoma.

Abstract：

BACKGROUND & AIMS:Recent studies indicate that kringle 1-5 has a potent and specific antiangiogenic activity. Here, we investigated the antitumor effect of kringle 1-5 gene transfer on hepatocellular carcinoma in mice. METHODS:The inhibitory effect of kringle 1-5 protein on proliferation of bovine capillary endothelial cells was evaluated by a tetrazolium-based assay. To study tumor growth, intrahepatic metastasis, and survival, liposome/kringle 1-5 complementary DNA complexes were injected intravenously in nude mice preimplanted with 1 of 3 hepatoma cell lines into the liver. Production of kringle 1-5 was tested by immunohistochemistry and Western blotting. Intratumoral vessel density was quantified. Expression of vascular endothelial growth factor, angiopoietin-1, and angiopoietin-2 in tumors was examined by Western blotting. Serum alanine aminotransferase and alpha-fetoprotein levels and body weights were measured. RESULTS:Proliferation of bovine capillary endothelial cells was inhibited by purified kringle 1-5 in a dose-dependent manner. Gene transfer of kringle 1-5 caused a significant reduction in vessel density with suppression of tumor growth of the 3 hepatoma cell lines and serum alpha-fetoprotein levels, prolonged the survival period, and reduced the number of intrahepatic metastases. Among the analyzed angiogenic factors, kringle 1-5 reduced angiopoietin-2 expression levels. Expression of kringle 1-5 protein was detected on hepatoma cells and hepatocytes in the liver. However, it did not alter serum alanine aminotransferase levels and body weights, suggesting kringle 1-5 lacks severe side effects. CONCLUSIONS:Antiangiogenic gene therapy with kringle 1-5 complementary DNA is a promising safe and effective strategy for suppression of growth of hepatocellular carcinoma.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

Torimura T,Ueno T,Kin M,Taniguchi E,Nakamura T,Inoue K,Sakata R,Hashimoto O,Sakamoto M,Ohira H,Kumashiro R,Sata M,Yano H,Kojiro M,Veitonmaki N,Cao Y

doi

10.1053/j.gastro.2006.02.020

subject

Has Abstract

pub_date

2006-04-01 00:00:00

pages

1301-10

issue

4

eissn

0016-5085

issn

1528-0012

pii

S0016-5085(06)00282-4

journal_volume

130

pub_type

杂志文章

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