PHARMACOLOGICAL INHIBITION OF GELATINASE-B INDUCTION AND TUMOR-CELL INVASION

The 92 kDa matrix metalloproteinase (gelatinase B, MMP-9) plays a majo r role in the facilitation of tumor metastasis and in inflammatory dis orders characterized by excessive matrix protein destruction. MMP-9 is transcriptionally induced in multiple cell types by exposure to the i nflammatory mediators bacterial endotoxin, interleukin-1 (IL-1) or tum or necrosis factor-alpha (TNF-alpha). CT-2519, (1-(5-isothiocyanatohex yl)-3,7-dimethylxanthine), a synthetic small molecule from an anti-inf lammatory compound library, was evaluated for its effect on endotoxin and cytokine-induced MMP-9 synthesis by a monocytic leukemic cell line , THP-1, and a monocyte/macrophage line, RAW 264.7. CT-2519 dose-depen dently inhibited endotoxin and cytokine-induced synthesis of MMP-9 by these cells. Furthermore, both MMP-9 secretion and matrix invasion by cells of a human fibrosarcoma cell line, HT-1080, were inhibited by CT -2519 in a dose-dependent manner. Northern blot analyses and studies u tilizing MMP-9 promoter constructs indicated that the inhibitory actio n of CT-2519 occurs at the level of transcriptional suppression. Given the observation that cellular activation by endotoxin, IL-1 and TNF-a lpha may be mediated, at least in part, through induction of certain s pecies of phosphatidic acid (PA), the effect of CT-2519 on lipid level s was analyzed. CT-2519 effectively reduced endotoxin-mediated increas es in particular cellular lipid levels. Pharmacologic modulation of cy tokine-dependent gene products, such as MMP-9, may offer an important therapeutic approach to the treatment of neoplastic and inflammatory d isorders. (C) 1996 Wiley-Liss, Inc.