INHIBITION OF ORGAN INVASION BY THE MATRIX METALLOPROTEINASE INHIBITOR BATIMASTAT (BB-94) IN 2 HUMAN COLON-CARCINOMA METASTASIS MODELS

The effect of the matrix metalloproteinase inhibitor batimastat was ev aluated in two human colorectal cancer metastasis models involving: (a ) the liver-invasive tumor C170HM(2) and (b) the lung-invasive tumor A P5LV, both of which have been shown to express the M(r) 72,000 type TV collagenase. Batimastat at concentrations between 0.01 and 3.0 mu g/m l had no direct cytotoxic effects on the in vitro growth of the cell l ines. In the liver-invasive tumor model, batimastat administered i.p. from day 10 to termination of the therapy (day 39) at 40 mg/kg reduced both the mean number of liver tumors (35% of vehicle-treated control; P < 0.05) and the cross-sectional area of the tumors (43% of vehicle- treated control; P < 0.05). In the lung-invasive tumor model, batimast at administered daily (40 mg/kg i.p.) significantly reduced tumor weig ht within the lung (72% of vehicle-treated control; P < 0.05) but did not significantly affect nodule number. In the latter model, in which the take rate was unaffected, tumor cells were introduced into the lat eral tail vein, and lung localization may have been a physical phenome non not involving invasion. In the former model, tumor cells were intr oduced directly into the peritoneal cavity, and from there the cells a dhered to and invaded the liver capsule. Because the take rate is sign ificantly reduced, it may be that the matrix metalloproteinases are in volved in this process. Batimastat may be a therapeutic modality for t he treatment of colorectal cancer metastasis.