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.