Matrix metalloproteinases (
MMPs) have been implicated in the invasion,
metastasis, and angiogenesis associated with human
cancer by mediating the degradation of extracellular matrix components. In this paper, we report data that show that
BAY 12-9566, a novel inhibitor of
MMPs, inhibits angiogenesis,
tumor regrowth, and the growth of lung
metastases.
BAY 12-9566, at 15-100 microM, inhibited tubule formation by human endothelial cells in an in vitro model, but did not prevent the proliferation of endothelial and human
breast cancer cells. In the MDA-MB-435
human mammary carcinoma xenograft model, in which the primary
tumor is transplanted into the murine mammary fat pad,
BAY 12-9566, administered daily at a dose of 100 mg/kg/day p.o. after resection of the primary
tumor, inhibited local
tumor regrowth by 58% without causing any toxic effect. In addition,
BAY 12-9566 treatment inhibited the number and volume of lung
metastases by 57 and 88%, respectively. These effects were highly correlated with the serum concentration of
BAY 12-9566 at the end of treatment. The serum of the treated animals, harvested 24 h after the last treatment, and the
tumor regrown at the site of
tumor transplant in the treated animals, contained less
protein with MMP-9 activity (as measured in a
gelatin zymography assay) than the corresponding controls. However, no difference in the activity of MMP-2 was observed. Although all clinical trials in
cancer involving
BAY 12-9566 have been halted, this
MMP inhibitor has never been used in clinical trials in
breast cancer. These results suggest that the novel
MMP inhibitor BAY 12-9566 maybe a useful and safe oral treatment for
breast cancer, adjunctive to surgery.