The potential for a selective cyclooxygenase-2 inhibitor in the prevention of liver metastasis in human colorectal cancer.
In a previous report we noted that cyclooxygenase-2 (COX-2) expression in clinical colorectal cancer is closely related to liver metastasis and survival. The aim of the present study was to clarify the role of COX-2 in liver metastasis and to examine the potential for a selective COX-2 inhibitor as a novel therapeutic agent in the treatment of colorectal cancer.


METHODS
COX-2 expression of 6 kinds of human colon cancer cell lines, with various potentials for liver metastasis, were assessed by Western blot and reverse transcriptase polymerase chain reaction (RT-PCR). In human tumor xenografts/severe combined immune-deficient (SCID) mouse, we examined the effects of a selective COX-2 inhibitor (JTE-522) on tumor growth or liver metastasis of HT-29, a highly-metastatic cell line, or on COLO205, a non-metastatic cell line. The effect of JTE-522 on vascular endothelial growth factor (VEGF) expression and the activity of matrix metalloproteinases (MMPs) in HT-29 and COLO205 were assessed by enzyme-linked immunosorbent assay (ELISA) and gelatin zymography, respectively.


RESULTS
COX-2 was expressed in all metastatic cell lines but not in the non-metastatic lines. JTE-522 prevented the liver metastasis of HT-29, but not the subcutaneous growth of HT-29 and COLO205 in SCID mice. In vitro, JTE-522 suppressed VEGF expression, but did not affect MMP production in HT-29; an inhibitory effect was not found in COLO205.


CONCLUSIONS
A selective COX-2 inhibitor of JTE-522, was found to prevent liver metastases of colon cancer by suppressing VEGF expression, and therefore, COX-2 possibly plays an important role in liver metastasis of human colon cancer via the regulation of VEGF expression.
Yamauchi
Takeyoshi
T
Department of Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Watanabe
Masahiko
M
Hasegawa
Hirotoshi
H
Nishibori
Hideki
H
Ishii
Yoshiyuki
Y
Tatematsu
Hideki
H
Yamamoto
Kentaro
K
Kubota
Tetsuro
T
Kitajima
Masaki
M
D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D019073:HT29 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008113:Liver Neoplasms / Q000201:enzymology / Q000517:prevention & control* / Q000556:secondary*; D008222:Lymphokines / Q000096:biosynthesis; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D008565:Membrane Proteins; D051379:Mice; D016513:Mice, SCID; D010080:Oxazoles / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023041:Xenograft Model Antitumor Assays; D000096926:Benzenesulfonamides
D001557:Benzenesulfonates; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008222:Lymphokines; D020782:Matrix Metalloproteinases; D008565:Membrane Proteins; D010080:Oxazoles; D011451:Prostaglandin-Endoperoxide Synthases; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C110453:4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide; D000096926:Benzenesulfonamides; C496540:PTGS2 protein, human