Antithrombin reduces reperfusion-induced hepatic metastasis of colon cancer cells.
OBJECTIVE
To examine whether antithrombin (AT) could prevent hepatic ischemia/reperfusion (I/R)-induced hepatic metastasis by inhibiting tumor necrosis factor (TNF)-alpha-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-alpha and E-selectin mRNA in hepatic tissue, serum fibrinogen degradation products and hepatic tissue levels of 6-keto-PGF(1alpha), a stable metabolite of PGI2, were measured.


RESULTS
AT inhibited increases in hepatic metastasis of tumor cells and hepatic tissue mRNA levels of TNF-alpha 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-PGF(1alpha) 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.


CONCLUSIONS
AT might reduce I/R-induced hepatic metastasis of colon cancer cells by inhibiting TNF-alpha-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.
Kurata
Masanao
M
Department of Surgery, Functional and Regulatory Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba Tennoudai 1-1-1, Tsukuba, Japan.
Okajima
Kenji
K
Kawamoto
Toru
T
Uchiba
Mitsuhiro
M
Ohkohchi
Nobuhiro
N
D015121:6-Ketoprostaglandin F1 alpha / Q000032:analysis; D000818:Animals; D000991:Antithrombins / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D019040:E-Selectin / Q000235:genetics; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D008114:Liver Neoplasms, Experimental / Q000517:prevention & control* / Q000556:secondary*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010875:Pipecolic Acids / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D015424:Reperfusion; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000991:Antithrombins; D019040:E-Selectin; D005338:Fibrin Fibrinogen Degradation Products; D010875:Pipecolic Acids; D012333:RNA, Messenger; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D015121:6-Ketoprostaglandin F1 alpha; C049453:OP 2507; D001120:Arginine; D011464:Epoprostenol; C031942:argatroban