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 metallop roteinase (MMP) inhibitor prinomastat (AG3340) on tumor progression using a n 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, intraper itoneally twice daily for 21 days, reduced primary tumor volume significant ly to 19.0 (+/-7.7)% of control, with induction of necrosis, differentiatio n, and fibrotic tissue in the pancreatic tumors. Invasion was not observed in 63% of prinomastat-treated mice, and metastases were reduced markedly. S urprisingly, prinomastat-treated tumors had on average higher microvessel d ensities as a consequence of an increased angiogenesis in perinecrotic tumo r areas. We conclude that prinomastat is highly effective in inhibiting pan creatic carcinoma growth and progression in an orthotopic cancer model. Thi s model appears to be a valuable tool to investigate the potency of novel a ntimetastatic strategies in pancreatic ductal adenocarcinoma by specificall y targeting certain MMPs. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.