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 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.
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015152:Blotting, Northern; D015153:Blotting, Western; D002216:Captopril / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D017364:Collagenases / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000378:metabolism; D005260:Female; D005780:Gelatin / Q000378:metabolism; D018093:Gelatinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000556:secondary; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009368:Neoplasm Transplantation; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000627:therapeutic use; D015996:Survival Rate; D013876:Thiophenes / Q000627:therapeutic use*