A SYNTHETIC MATRIX METALLOPROTEINASE INHIBITOR DECREASES TUMOR BURDENAND PROLONGS SURVIVAL OF MICE BEARING HUMAN OVARIAN-CARCINOMA XENOGRAFTS

We have examined the effect of a synthetic low-molecular-weight matrix metalloproteinase inhibitor, hiomethyl)-succinyl]-L-phenylalanine-N-m ethylamide (BB-94), on human ovarian carcinoma xenografts growing in n ude mice. The xenografts grew as thick intraperitoneal mucinous ascite s containing free-floating tumor cell clumps. The ascites increased in volume, causing death approximately 3 weeks after introduction. Treat ment with BB-94 caused resolution of ascitic disease. Tumor burden was dramatically reduced, and survival increased 5-6-fold. The increase i n survival was dose dependent. The effects observed with BB-94 appeare d to be due to its matrix metalloproteinase inhibiting effects, inasmu ch as its inactive diastereoisomer had no effect on tumor biology. Fol lowing treatment with BB-94, free-floating clumps of tumor cells becam e surrounded by a capsule of host cells. These clumps of tumor cells t ypically formed one small (approximately 8 mm) avascular tumor of brig ht white appearance loosely attached to fat in the peritoneum. Tumor c ells within these capsules often appeared to be necrotic. Gel substrat e analysis demonstrated that activated M(r) 92,000 type IV collagenase was present in the xenografts. We propose that inhibition of this enz yme causes the transition of ascites to solid tumors, concomitantly sl owing tumor cell growth and allowing the development of tumor stroma.