Preventive Effect of Matrix Metalloproteinase Inhibitor, R‐94138, in Combination with Mitomycin C or Cisplatin on Peritoneal Dissemination of Human Gastric Cancer Cell Line TMK‐1 in Nude Mice

Abstract

R-94138, a matrix metalloproteinase inhibitor, was examined for the ability to prevent peritoneal dissemination of a human gastric cancer xenograft, TMK-1. When the supernatant of a co-culture of TMK-1 cells and human normal fibroblast cells was subjected to gelatin zymography, it was clear that the protein expression of MMP-2 had been inhibited by R-94138. When TMK-1 was injected intraperitoneally (i.p.) into nude mice at 5 x 10(5) cells/body, the resulting peritoneal dissemination mimicked clinical carcinomatous peritonitis. When the maximum tolerated dose of mitomycin C (MMC) or cisplatin (DDP) was given 12 h after the tumor inoculation, peritoneal dissemination was completely inhibited, while the effect of R-94138 was limited when it was given i.p. at a dose of 20 mg/kg in a schedule of q.d. x 5 starting 12 h after tumor injection. MMC and DDP also suppressed peritoneal dissemination when they were administered 1 week after the tumor inoculation at a single dose of 2 and 3 mg/kg i.p., respectively. R-94138 inhibited peritoneal dissemination when it was administered i.p. at a dose of 30 mg/kg in a schedule of q.d. x 5 starting from 1 week after tumor injection. The combination of MMC and R-94138 increased the preventive effect on peritoneal dissemination. R-94138 seems to be a promising candidate to prevent peritoneal dissemination of gastric cancer.