A synthetic matrix metalloproteinase inhibitor decreases tumor burden and prolongs survival of mice bearing human ovarian carcinoma xenografts.
We have examined the effect of a synthetic low-molecular-weight matrix metalloproteinase inhibitor, [4-(N-hydroxyamino)-2R-isobutyl-3S- (thiopen-2-ylthiomethyl)-succinyl]-L-phenylalanine-N-meth yla mide (BB-94), on human ovarian carcinoma xenografts growing in nude mice. The xenografts grew as thick intraperitoneal mucinous ascites containing free-floating tumor cell clumps. The ascites increased in volume, causing death approximately 3 weeks after introduction. Treatment with BB-94 caused resolution of ascitic disease. Tumor burden was dramatically reduced, and survival increased 5-6-fold. The increase in survival was dose dependent. The effects observed with BB-94 appeared to be due to its matrix metalloproteinase inhibiting effects, inasmuch as its inactive diastereoisomer had no effect on tumor biology. Following treatment with BB-94, free-floating clumps of tumor cells became surrounded by a capsule of host cells. These clumps of tumor cells typically formed one small (approximately 8 mm) avascular tumor of bright white appearance loosely attached to fat in the peritoneum. Tumor cells within these capsules often appeared to be necrotic. Gel substrate analysis demonstrated that activated Mr 92,000 type IV collagenase was present in the xenografts. We propose that inhibition of this enzyme causes the transition of ascites to solid tumors, concomitantly slowing tumor cell growth and allowing the development of tumor stroma.
Davies
B
B
Biological Therapy Laboratory, Imperial Cancer Research Fund, Lincoln's Inn Fields, London, England.
Brown
P D
PD
East
N
N
Crimmin
M J
MJ
Balkwill
F R
FR
D000368:Aged; D000818:Animals; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D005109:Extracellular Matrix / Q000201:enzymology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016019:Survival Analysis; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects
D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D008666:Metalloendopeptidases