[Effect of intraperitoneal chemotherapy on experimental peritoneal dissemination of gastric cancer].

In vitro chemosensitivity test using a collagen-gel method was done on 165 primary gastric cancers. All of 5-FU, CBDCA, CDDP and docetaxel showed a high sensitivity. The effects of per oral (po) administration of TS-1, a combination of po TS-1 and intraperitoneal (ip) administration of CDDP, ip 5-FU and ip docetaxel, were evaluated in athymic mice bearing peritoneal dissemination of a gastric cancer cell line (MKN-45-P that shows a high rate of metastasis to the peritoneal cavity of nude mice). Nude mice were inoculated by ip with 10(7) MKN-45-P cells. No survival benefit was obtained after po administration of TS-1 (12 mg/kg) alone or ip CDDP alone. However, a combination of po TS-1 (8 mg/kg x 10 days, from day 3) and ip CDDP (3.5 mg/kg, day 6 and 13) showed a significant survival improvement than that of po TS-1 or ip CDDP treatment alone. ip administration of 30 mg/kg (3 times/week x 3 weeks) or 15 mg/kg (6 times/week x 3 weeks) of 5-FU significantly improved the survival of mice bearing MKN-45-P. 5-FU concentration of ascites after ip administration of 30 mg/kg of 5-FU was 600-fold higher than po administration of 12 mg/kg of TS-1 at peak level. ip injections of docetaxel of 8 mg/kg, and 2 mg/kg improved the survival of 4 and 1 mice, respectively, and they were tumor-free on day 90. Survival of mice treated with ip injection of CBDCA (100 mg/kg, on day 3, or 50 mg/ kg on day 3 and 10) was significantly better than the control group. These results suggest the potential of po TS-1 + ip CDDP, ip 5-FU, ip docetaxel and ip CBDCA administration for the treatment of peritoneal dissemination of gastric cancer.

Expression of collagenase-3 (matrix metalloproteinase-13) in human gastric cancer.

BACKGROUND: Collagenase-3 (matrix metalloproteinase-13; MMP-13) is a recently identified member of the matrix metalloproteinases (MMPs) with broad substrate specificity, and a potential role in tumor metastasis and invasion has been proposed for this enzyme. To date, in gastrointestinal tract tumors, collagenase-3 expression has been reported only in esophageal carcinoma; the presence and possible implications of this enzyme in the progression of gastric cancer are unknown. METHODS: In this study, MMP-13 mRNA expression was analyzed in a series of 110 matched gastric adenocarcinomas and the corresponding adjacent normal mucosae as well as in nine gastric cancer cell lines. In addition, the mRNA expression of gelatinase a (MMP-2) and membrane type-1 matrix metalloproteinase (MT1-MMP), two MMPs which have the ability to activate MMP-13 in vitro, was also examined in the same cases and cell lines. the production and localization of MMP-13, MMP-2, and MT1-MMP were investigated by immunohistochemistry, immunofluorescence, western blot analysis, and zymography. RESULTS: MMP-13 mrna was expressed in 23 of the 110 carcinomas (21%), and MT1-MMP mRNA was expressed in 45 (40%), but no MMP-13 or MT1-MMP mRNA was detected in any of the normal mucosae. Also, eight of the nine gastric cancer cell lines expressed mRNA of MMP-13, and in each cell line there was coordinate expression with either MT1-MMP or MMP-2 mRNA. MMP-13 and MT1-MMP were detected at the bases of invadopodia of the cultured cancer cells as well as in the invasive front of the tumors, as shown by immunofluorescence and immunohistochemistry, respectively. Western blot analysis revealed the presence of MMP-13 protein in those cell lines and carcinomas that expressed its mrna. on zymography, almost all cell lines that expressed MMP-13 showed gelatinolytic bands corresponding to the active form of MMP-13 or one of its intermediate forms. Also, zymographic analysis of the tumor specimens revealed strong gelatinolytic bands of MMP-13 and MMP-2, whereas these bands in normal mucosa were weak. There was no significant relationship between MMP-13 mRNA expression and histologic type, lymph node metastasis, wall invasion, or distant metastasis. However, patients with MMP-13 mRNA-positive tumors had a poorer prognosis than those with MMP-13-mrna-negative cancer. Furthermore, patients with simultaneous expression of MMP-13 and MT1-MMP mRNA showed the poorest prognosis, as compared with those having tumors expressing either MMP-13 or MT1-MMP, or neither MMP-13 nor MT1-MMP mRNA. CONCLUSION: These findings suggest that MMP-13 expression may contribute to the progression of gastric cancer, and its coordinate overexpression with MT1-MMP and/or MMP-2 may have a cooperative effect in the progression of gastric cancer.