Inhibition of gelatinase A (MMP-2) by batimastat and captopril reduces tumor growth and lung metastases in mice bearing Lewis lung carcinoma

We have examined the effects of the synthetic matrix metalloproteinase inhi bitor, batimastat (BB-94) and the angiotensin-converting enzyme inhibitor, captopril, on metalloproteinase activity of murine Lewis-lung-carcinoma cel ls (3LL) in vitro, and on local growth and lung metastasis of the same tumo r implanted intramuscularly in syngeneic C57BL/6 mice. The effect of BB-94 and captopril on the survival of the 3LL-tumor-bearing mice was also examin ed. Here we report that captopril treatment resulted in decreased transcrip tion and protein levels of gelatinase A by 3LL cells. Both BB-94 and captop ril also prevented substrate degradation by gelatinase A and B released in conditioned medium by cultured cells. Treatment of tumor-bearing animals wi th BB-94 (i.p.) or captopril (in drinking water) resulted in significant in hibition of the mean tumor volume (25 and 33% respectively) and of the mean lung metastasis number (26 and 29% respectively). When both agents were gi ven, they acted in synergy, resulting in 51 and 80% inhibition of tumor gro wth and metastasis. The survival time of the mice treated with both BB-94 a nd captopril was also significantly longer compared with the groups treated with each agent alone or with the vehicle. Our data support the hypothesis of an essential role of metalloproteinase(s) in the metastatic process. Mo reover, blockade of invasion, angiogenesis and other processes mediated by metalloproteinases may underlie the anti-tumor and antimetastatic effect of BB-94 and captopril and their combination. It is conceivable that this com bination could be tested in selected clinical conditions as an adjuvant mod ality to cytotoxic therapy. (C) 1999 Wiley-Liss, Inc.