Therapeutic effect of the matrix metalloproteinase inhibitor, batimastat, in a human colorectal cancer ascites model

Abstract

Summary The matrix metalloproteinase inhibitor batimastat was administered to a human colorectal cancer ascites model, which was initiated by injection of C170HM2 cells into the peritoneal cavity of SCID mice and resulted in solid tumour deposits and ascites formation. The cell line expressed both the 72 and 92 kDa forms of gelatinase by zymography. Batimastat administered from day 0 (40 mg kg-1) reduced the volume of ascites to 21 % of control in mice treated from day 0 (P <0.002) but not day 10. Formation of solid peritoneal deposits was significantly reduced to 77% of vehicle control when batimastat was administered from day 0 (P<0.01) and 69% of control when administered from day 10 (P<0.05). Thus, batimastat has the ability to reduce the volume of ascites forming in SCID mice injected intraperitoneally with the human colorectal cell line, C170HM2, when administered from day 0 but not from day 10. Solid peritoneal tumour deposits were significantly reduced in both treatment groups, highlighting the therapeutic potential of batimastat in this clinical condition.Keywords: metalloproteinase; colorectal cancer; batimastat A large body of evidence now suggests that matrix metalloproteinases (MMPs) play a role in the metastasis of tumour cells (Brown, 1993). Secretion of these enzymes by both normal and malignant cells is in the form of a latent precursor, which is activated by removal of an amino terminal domain (Stetler-Stevenson et al., 1989). These enzymes are implicated in the breakdown of extracellular matrix and vascularisation, which are both critical for successful metastasis, and recent clinical studies have shown MMP to play a role in the spread of human tumour cells Davies et al., 1993).The role of individual enzymes from the MMP family, in both the growth and metastatic spread of colorectal tumours, has been investigated. Activity of type I fibrillar collagenase, a member of the MMP family, has been shown to correlate with histological grade (van der Strappen, 1990). The 72 kDa gelatinase, which breaks down type IV collagenase of basement membrane, correlates with tumour progression, and mRNA studies have revealed the presence of this enzyme in the tissue stroma adjacent to the invasive edge of the cancer (D'Errico et al., 1991; Poulson et al., 1992). The 92 kDa form of gelatinase has been demonstrated by immunocytochemistry to be widespread in colorectal carcinoma, especially in tumours of advanced stage (Jeziorska et al., 1994). In the same study, expression of the enzyme at specific sites in the tumour has been shown to be inversely related to the localisation of type IV collagen. Furthermore, the 92 kDa gelatinase is elevated in the plasma of colon cancer patients (Zucker et al., 1993). In a study evaluating stromelysins 1 and 2 and matrilysin (PUMP-1) expression in colorectal cancer, the mRNA of the latter enzyme was expressed in 75% of colon carcinomas, whereas the mRNA of the former was not detected (McDonnell et al., 1991). In a recent study, stromelysin 3 mRNA was overexpressed in primary col...

Role of Matrix Metalloproteinases and Their Inhibitors in Pancreatic Cancer

“…Subsequent autopsy studies demonstrated that the tumour was encapsulated in a dense fibrous stro ma with necrosis of some tumour cells [90]. Similar results have been reported in a human colorectal ascites xenograft model [91]. Batimastat was also shown to inhib it locorégional regrowth and métastasés of a human breast carcinoma (MDA-MB-435) following resection in athym ie nude mice [92], Wang et al [93] orthotopically implanted fragments of human colonic carcinoma into athymie nude mice.…”

Synthetic inhibitor of matrix metalloproteinases (batimastat) reduces prostate cancer growth in an orthotopic rat model

“…Watson et al [33] evaluated the effect of batimastat on a human colorectal cancer ascites model, which was initiated by injection of C170HM 2 cells into the peritoneal cavity of severe combined immunodeficient (SCID) mice. The inoculation of ascites cells resulted in solid tumor deposits and ascites formation.…”

Efficacy of the MMP inhibitor MMI270 against lung metastasis following removal of orthotopically transplanted human colon cancer in rat

“…Thus, their antitumor activity might be enhanced when used in combination with conventional chemotherapeutic agents. Despite impressive preclinical anticancer activity [28][29][30][31][32] and the suggestion of biological activity in phase I and phase II trials, 33,34 the MMPIs as a single agent or in combination with chemotherapeutic agent have been disappointing thus far in randomized clinical trials for solid tumors. 35,36 However, given the role of MMPIs in colorectal tumorigenesis, the synthetic MMPIs could find an even more important role in primary and/or secondary colorectal cancer prevention than in the treatment of established disease.…”