BATIMASTAT, A SYNTHETIC INHIBITOR OF MATRIX METALLOPROTEINASES, POTENTIATES THE ANTITUMOR-ACTIVITY OF CISPLATIN IN OVARIAN-CARCINOMA XENOGRAFTS

Batimastat (also known as BB-94) is a synthetic matrix metalloproteina se inhibitor that has shown antineoplastic and antiangiogenic activity in various tumor models, In this study, two human ovarian carcinoma ( HOC) xenografts (HOC22 and HOC8) were used to investigate the effect o f batimastat on the antineoplastic activity of cisplatin, Both xenogra fts produced ascites and solid lesions in the peritoneal cavity of nud e mice, HOC cells were inoculated i.p. in nude mice, and treatment was started at different stages of the disease, Batimastat was administer ed alone or concurrently with or subsequent to cisplatin therapy, In a ll of the protocols, the response of HOC xenografts was confirmed by c ytological analysis of ascites and histological examination of the org ans in the peritoneal cavity, Treatment of nude mice bearing early-sta ge (3 days after tumor implantation) HOC22 or HOC8 with cisplatin or b atimastat alone delayed tumor growth and increased the survival time o f the mice, although all animals eventually died, In contrast, treatme nt with batimastat (60 mg/kg i.p. every other day, for a total of eigh t injections) concomitantly with cisplatin (4 mg/kg i.v., every 7 days for a total of three injections) completely prevented growth and spre ad of both xenografts, and all animals were alive and healthy on day 2 00, The potentiation of cisplatin's activity by batimastat was dose de pendent and was observed in the treatment of both advanced (7 days aft er tumor inoculation) and late-stage (20 days after inoculation) tumor , The administration of batimastat following cisplatin therapy also le d to significant improvement in the survival of mice compared to treat ment with cisplatin alone, These results suggest a potentiation of the antineoplastic activity of cisplatin by batimastat and support the us e of the two agents in combination in the treatment of ovarian cancer patients.