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Antithrombin reduces reperfusion-induced hepatic metastasis of colon cancer cells

World Journal of Gastroenterology 2006年第1期12卷 60-65页

作者： Masanao Kurata Kenji Okajima Toru Kawamoto Mitsuhiro Uchiba Nobuhiro Ohkohchi Department of Surgery Functional and Regulatory Medical SciencesGraduate School of Comprehensive Human SciencesUniversity ofTsukubaTsukubaJapan Department of Biodefense Graduate School of Medical SciencesNagoya City UniversityNagoyaJapan Department of Diagnostic Medicine Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan

AIM： To examine whether antithrombin （AT） could prevent hepatic ischemia/reperfusion （I/R）-induced hepatic metastasis by inhibiting tumor necrosis factor （TNF）-α-induced expression of E-selectin in rats. METHODS： hepatic I/R was induced in rats and mice by clamping the left branches of the portal vein and the hepatic artery. Cancer cells were injected intrasplenically. The number of metastatic nodules was counted on day 7 after I/R. TNF-α and E-selectin mRNA in hepatic tissue, serum fibrinogen degradation products and hepatic tissue levels of 6-keto-PGF1α, a stable metabolite of PGI2, were measured. RESULTS： AT inhibited increases in hepatic metastasis of tumor cells and hepatic tissue mRNA levels of TNF-α and E-selectin in animals subjected to hepatic I/R. Argatroban, a thrombin inhibitor, did not suppress any of these changes. Both AT and argatroban inhibited I/R-induced coagulation abnormalities. I/R-induced increases of hepatic tissue levels of 6-keto-PGF1α were significantly enhanced by AT. Pretreatment with indomethacin completely reversed the effects of AT. Administration of OP-2507, a stable PGI2 analog, showed effects similar to those of AT in this model. hepatic metastasis in congenital AT-deficient mice subjected to hepatic I/R was significantly increased compared to that observed in wild-type mice. Administration of AT significantly reduced the number of hepatic metastases in congenital AT-deficient mice. CONCLUSION： AT might reduce I/R-induced hepatic metastasis of colon cancer cells by inhibiting TNF-α-induced expression of E-selectin through an increase in the endothelial production of PGI2. These findings also raise the possibility that AT might prevent hepatic metastasis of tumor cells if administered during the resection of liver tumors.

关键词： Antithrombin,reperfusion Metastasis factor-aE-selectin hepatic ischemia/prostacyclin Tumor necrosis factor-α

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