Correlation of antiangiogenic and antitumor efficacy of N-biphenyl sulfonyl-phenylalanine hydroxiamic acid (BPHA), an orally-active, selective matrixmetalloproteinase inhibitor

The antiangiogenic activity and antitumor efficacy of a newly developed mat rix metalloproteinase (MMP) inhibitor were examined. N-biphenyl sulfonyl-ph enylalanine hydroxiamic acid (BPHA) potently inhibits MMP-2, -9, and -14, b ut not MMP-1, -3, or -7. In contrast, (-)BPHA, an enantiomer of BPHA, was i nactive against all MMPs tested. Daily oral administration of 200 mg/kg BPH A, but not (-)BPHA in mice resulted in potent inhibition of tumor-induced a ngiogenesis, primary tumor growth, and liver metastasis. The growth inhibit ion activity of BPHA was 48% and 45% in a B16-BL6 melanoma and F2 hemangio- endothelioma model, respectively. BPHA also showed 42% inhibition of the li ver metastasis of C-1H human colon carcinoma cells. These results indicate that selective MMP inhibition is correlated with antiangiogenic and antitum or efficacy and that the selective MMP inhibitor BPHA has therapeutic poten tial.