Inhibition of organ invasion by the matrix metalloproteinase inhibitor batimastat (BB-94) in two human colon carcinoma metastasis models.

ABSTRACT

The effect of the matrix metalloproteinase inhibitor batimastat was evaluated in two human colorectal cancer metastasis models involving (a) the liver-invasive tumor C170HM2 and (b) the lung-invasive tumor AP5LV, both of which have been shown to express the M(r) 72,000 type IV collagenase. Batimastat at concentrations between 0.01 and 3.0 micrograms/ml had no direct cytotoxic effects on the in vitro growth of the cell lines. 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, batimastat administered daily (40 mg/kg i.p.) significantly reduced tumor weight 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 lateral tail vein, and lung localization may have been a physical phenomenon not involving invasion. In the former model, tumor cells were introduced directly into the peritoneal cavity, and from there the cells adhered to and invaded the liver capsule. Because the take rate is significantly reduced, it may be that the matrix metalloproteinases are involved in this process. Batimastat may be a therapeutic modality for the treatment of colorectal cancer metastasis.