Reduced angiogenesis in peritoneal dissemination of gastric cancer through gelatinase inhibition.
Marimastat is a broad-spectrum matrix metalloproteinase (MMP) inhibitor that inhibits almost all major MMPs, key enzymes in gastric cancer invasion and metastasis. We investigated the ability of marimastat to inhibit tumor angiogenesis in the severe combined immuno-deficient (SCID) mouse/human gastric cancer model of peritoneal dissemination. A human stomach adenocarcinoma cell line, TMK-1, was injected intraperitoneally into SCID mice. On the 7th day after tumor inoculation, the administration of marimastat (27 mg/kg/day) was initiated and the treatment was continued for 2 weeks using subcutaneously-inoculating mini-osmotic pumps. On the 21st day, the mice were killed and the disseminated nodules were evaluated. Total weights, numbers, and the microvascular density of the disseminating nodules were significantly lower in mice treated with marimastat compared to the control group. Film in situ zymography demonstrated that net gelatinolytic activity in the tissues was weaker in treated-group nodules than in control-group nodules. Thus, our results suggested that marimastat inhibited peritoneal dissemination of human gastric cancer cells through inhibition of tumor angiogenesis, possibly involving the down-regulation of gelatinases, in SCID mice injected with human gastric cancer cells.
Wada
Norihito
N
Department of Surgery, School of Medicine, Keio University, Tokyo, Japan.
Otani
Yoshihide
Y
Kubota
Tetsuro
T
Kimata
Masaru
M
Minagawa
Akiko
A
Yoshimizu
Nobunari
N
Kameyama
Kaori
K
Saikawa
Yoshiro
Y
Yoshida
Masashi
M
Furukawa
Toshiharu
T
Fujii
Masato
M
Kumai
Koichiro
K
Okada
Yasunori
Y
Kitajima
Masaki
M
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018093:Gelatinases / Q000037:antagonists & inhibitors*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D008833:Microcirculation; D009389:Neovascularization, Pathologic; D009995:Osmosis; D010537:Peritoneum / Q000201:enzymology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D013274:Stomach Neoplasms / Q000473:pathology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C100342:marimastat; D018093:Gelatinases