Inhibitory effect of a matrix metalloproteinase inhibitor on growth and spread of human pancreatic ductal adenocarcinoma evaluated in an orthotopic severe combined immunodeficient (SCID) mouse model.
The present study was aimed at evaluating the effect of the matrix metalloproteinase (MMP) inhibitor prinomastat (AG3340) on tumor progression using an orthotopic pancreatic carcinoma model in severe combined immunodeficient mice. In controls, receiving vehicle only, the poorly differentiated ductal adenocarcinoma invaded into adjacent organs and metastasized to different sites in the abdomen and to the lungs. Treatment with prinomastat, intraperitoneally twice daily for 21 days, reduced primary tumor volume significantly to 19.0 (+/-7.7)% of control, with induction of necrosis, differentiation, and fibrotic tissue in the pancreatic tumors. Invasion was not observed in 63% of prinomastat-treated mice, and metastases were reduced markedly. Surprisingly, prinomastat-treated tumors had on average higher microvessel densities as a consequence of an increased angiogenesis in perinecrotic tumor areas. We conclude that prinomastat is highly effective in inhibiting pancreatic carcinoma growth and progression in an orthotopic cancer model. This model appears to be a valuable tool to investigate the potency of novel antimetastatic strategies in pancreatic ductal adenocarcinoma by specifically targeting certain MMPs.
Department of Hematology and Oncology, University of Göttingen, Robert-Koch-Strasse 40, D-37075, Göttingen, Germany. falves@gwdg.de
F
F
Alves
U
U
Borchers
B
B
Padge
H
H
Augustin
K
K
Nebendahl
G
G
Klöppel
L F
LF
Tietze
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D016513:Mice, SCID; D009336:Necrosis; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009930:Organic Chemicals; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; D009930:Organic Chemicals; C113282:prinomastat