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Inhibition of Gelatinolytic Activity in Tumor Tissues by Synthetic Matrix Metalloproteinase Inhibitor: Application of Film in Situ Zymography

Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka 553-0002, Japan [M. I., R. M., H. T., M. M., Y. Tak., T. Y.], and Ashigara Research Laboratories, Fuji Photo Film Co., Ltd., Kanagawa 250-0193, Japan [Y. Tam., R. N.]

Inhibition of gelatinolytic activity in implanted tumor tissues by oral administration of N-biphenyl sulfonyl-phenylalanine hydroxamic acid (BPHA), a selective matrix metalloproteinase (MMP) inhibitor, was demonstrated by means of film in situ zymography (FIZ). Active-MMP-2 but not pro-MMP-2 showed gelatinolytic activity in FIZ, whereas both forms of MMP-2 were found to be active in conventional zymography. A mixture of either tissue inhibitors of metalloproteinase-2 or BPHA with active-MMP-2 resulted in inhibition of gelatinolytic activity in FIZ but not in zymography. Thus, FIZ, but not zymography, could detect net MMP activity in tumor tissues. When a specimen from Ma44 human lung cancer xenograft was subjected to FIZ, gelatinolytic activity was markedly detected with precise localization in the tumor tissues. The gelatinolytic activity detected in Ma44 tumor tissues was found to be mainly derived from MMPs because the gelatin-degrading activity was inhibited by pretreatment of the tumor specimen with MMP inhibitors. Oral administration of BPHA but not (-)BPHA, an enantiomer of BPHA lacking MMP inhibitory activity, successfully inhibited the MMP activity localized in Ma44 tumor tissues in both a dose-dependent and time-dependent manner. The data presented in this report showed for the first time that oral administration of synthetic MMP inhibitor could inhibit the net activity of MMP activity in tumor tissues, suggesting the usefulness of the FIZ technique for determining the effective dose of MMP inhibitor in clinical studies.

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