Matrix metalloproteinase inhibition prevents colon cancer peritoneal carcinomatosis development and prolongs survival in rats

Matrix metalloproteinases (MMP) are enzymes responsible for extracellular m atrix degradation which play a role in cancer progression and metastatic sp reading. We investigated the effects of the MMP inhibitor, batimastat, irt vitro on the proliferation and invasiveness of the rat colon cancer cell li ne DHD/K12, and in vivo on the growth of an aggressive model of peritoneal carcinomatosis producing haemorrhagic ascites and metastases, obtained in t he rat by i.p. injection of DHD/K12 cells. MMP production was studied in co nditioned culture media, solid tumors and ascitic fluid, In vivo, after inj ection of tumor cells on day 0, rats received i.p. daily either batimastat (30 mg/kg) or equal volume of vehicle from day 2 until killing on day 43 (s eries I) or from day 13 until death (series II). The grade of peritoneal ca rcinomatosis, ascite volume, number and size of liver metastases were evalu ated in both series, and survival in series II. MMPs-1, -2 and -9 were iden tified in culture media, tumors and ascites, In vitro, batimastat did not m odify DHD/K12 cell proliferation and slightly reduced cell invasion. In viv o, in series I, batimastat treatment totally prevented peritoneal carcinoma tosis and liver metastasis development. In series II, it significantly prol onged survival (P < 0.0002) and reduced peritoneal carcinomatosis (P < 0.00 1) and hepatic metastases number as compared with controls. However, batima stat-treated rats of the two series had peritoneal inflammation with marked ascites, Nevertheless, inhibition of MMP is a new therapeutic approach whi ch may be promising in treatment of microtumors as in more advanced cancer stages.