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

Abstract

We have examined the effects of the synthetic matrix metalloproteinase inhibitor, batimastat (BB‐94) and the angiotensin‐converting enzyme inhibitor, captopril, on metalloproteinase activity of murine Lewis‐lung‐carcinoma cells (3LL) in vitro, and on local growth and lung metastasis of the same tumor 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 examined. Here we report that captopril treatment resulted in decreased transcription and protein levels of gelatinase A by 3LL cells. Both BB‐94 and captopril also prevented substrate degradation by gelatinase A and B released in conditioned medium by cultured cells. Treatment of tumor‐bearing animals with BB‐94 (i.p.) or captopril (in drinking water) resulted in significant inhibition of the mean tumor volume (25 and 33% respectively) and of the mean lung metastasis number (26 and 29% respectively). When both agents were given, they acted in synergy, resulting in 51 and 80% inhibition of tumor growth and metastasis. The survival time of the mice treated with both BB‐94 and 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. Moreover, blockade of invasion, angiogenesis and other processes mediated by metalloproteinases may underlie the anti‐tumor and anti‐metastatic effect of BB‐94 and captopril and their combination. It is conceivable that this combination could be tested in selected clinical conditions as an adjuvant modality to cytotoxic therapy. Int. J. Cancer 81:761–766, 1999. © 1999 Wiley‐Liss, Inc.

Angiotensin inhibition and malignancies: a review

“…Neither the injections of bestatin and captopril nor bestatin in combination with captopril influenced the number of lung tumour colonies. 39 According to Prontera et al, 40 the effect of the synthetic MMP-2 inhibitor batimastat and captopril resulted in 51 and 80% inhibition, respectively, of tumour growth and metastases. Captopril pretreatment augmented the antitumour action of cyclophosphamide, expressed in terms of the survival time and the number of cured mice.…”

Combination antiangiogenesis therapy with marimastat, captopril and fragmin in patients with advanced cancer

“…Epidemiological studies suggest that the incidence of cancer and cancer deaths are lower in hypertensive patients taking ACE inhibitors than in those treated with other classes of antihypertensives (Lever et al, 1998). Captopril has been shown to inhibit matrix metalloproteases 2 and 9, which are involved in the angiogenic process (Prontera et al, 1999).…”

“…The rationale for the combination of captopril and the matrix metalloprotease inhibitor (MMPI) marimastat in this study comes from pre-clinical studies using the murine Lewis lung carcinoma model (Prontera et al, 1999). When captopril was administered with the MMPI Batimastat, the combination had synergistic activity both in inhibition of matrix metalloproteases 2 and 9 in the tumour cells and in blocking tumour growth and metastasis.…”

Low molecular weight inhibitors of matrix metalloproteinases can enhance the expression of matrix metalloproteinase‐2 (gelatinase A) without inhibiting its activation

“…To prevent these activities in a disease setting, interference with the activity of MMPs has been proposed as a therapeutic strategy. Synthetic low molecular weight inhibitors of these enzymes, therefore, have been tested in model systems and, in a number of studies, a clear inhibition of tumor growth was reported, [2][3][4][5][6] thus providing support for the clinical use of such inhibitors. However, in contrast, some studies demonstrated that inhibition of MMP activity had no effect or even led to an augmentation of the tumor.…”