Reduction of in vivo tumor growth by MMI-166, a selective matrix metalloproteinase inhibitor, through inhibition of tumor angiogenesis in squamous cell carcinoma cell lines of head and neck

Matrix metalloproteinases (MMPs) have been implicated in tumor invasion, metastasis, and angiogenesis. We have recently shown that MMI-166, a new orally active MMP inhibitor specific for MMP-2 and -9, suppressed experimental metastasis of Lewis lung cancer, C-H1 human colon cancer, and pancreatic cancer without affecting tumor growth in vitro. In the present study, we determined whether oral administration of MMI-166 reduces tumor growth not only in such tumors but also in squamous cell carcinoma of head and neck (SCCHN). MMI-166 inhibited both activity of MMP-2 and -9 without affecting steady state levels of their mRNAs in SCCHN. Interestingly, protein levels of MMP-2 and -9 from the cultures were drastically diminished by culturing with MMI-166. This was also observed in xenografts of MMI-166-administered mice. In addition, daily oral administration of MMI-166 (100 mg/kg) inhibited local tumor growth accompanied by the reduction of blood vessel density and Ki-67-positivity and increase in terminal deoxynucleotidyl transferase-mediated cUDP nick-end labeling (TUNEL)-positivity. These results suggested that orally administered MMI-166 reduced in vivo tumor growth of SCCHN through inhibition of angiogenesis and induction of apoptosis accompanied by the reduction of MMP productions and activities. Therefore, MMI-166 seems to be useful for tumor dormancy therapy of SCCHN.