Synthetic inhibitor of matrix metalloproteases decreases tumor growth and metastases in a syngeneic model of rat prostate cancer in vivo.
Members of the matrix metalloprotease (MMP) family are implicated in the progression of several malignancies including prostate cancer due to their ability to break down extracellular matrix (ECM) components. In this study, we have evaluated the ability of a synthetic MMP inhibitor (A-177430) to block tumor growth and metastases in a syngeneic model of rat prostate cancer. In an in vitro substrate assay, A-177430 exhibited nanomolar potency (IC(50) 2-6 nM) against the enzymatic activity of several MMPs. For in vivo studies, male Copenhagen rats were injected s.c. with Mat Ly Lu rat prostate cancer cells (1 x 10(6) cells ) into the right flank and animals were administered i.p.with different doses (10-100 mg/kg per day) of A-177430 for 16 days. Administration of A-177430 resulted in a dose-dependent decrease in tumor volume as compared to a control group of animals receiving vehicle alone. The maximum dose (100 mg/kg per day) of A-177430 exhibited complete arrest in tumor growth and prevented the development of macroscopic tumor metastases to lungs without exhibiting any noticeable side effects. Histologic examination of primary tumors from experimental animals showed extensive tumor necrosis and decreased tumor angiogenesis as determined by factor VIII staining of primary tumors following A-177430 treatment. These primary tumors from experimental animals also exhibited a significant increase in tumor cell DNA fragmentation as determined by TUNEL assay. Collectively, these results demonstrate the ability of MMP inhibitors to block tumor growth and metastases by blocking ECM degradation and by inhibiting tumor angiogenesis and promotion of prostate cancer cell apoptosis in vivo.
Rabbani
S A
SA
Departments of Medicine and Oncology, McGill University and Royal Victoria Hospital, Montreal Quebec, Canada.
Harakidas
P
P
Guo
Y
Y
Steinman
D
D
Davidsen
S K
SK
Morgan
D W
DW
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007797:Laminin / Q000378:metabolism; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
C411847:A 177430; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007797:Laminin; D061965:Matrix Metalloproteinase Inhibitors; D010456:Peptides, Cyclic; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen