Inhibition of Angiogenesis and regression of human pancreatic cancer by blockade of egf-r signal transduction in combination with gemcitabine

The purpose of this study was to evaluate whether down-regulation of EGF-R signaling pathway by an EGF-R tyrosine kinase inhibitor (CGP75166, daily, oral) or EGF-R antibody (C225, bi-weekly, intraperitoneal) can inhibit growth and metastasis of human pancreatic carcinoma in nude mice. We also investigated whether the efficacy of gemcitabine - first line chemotherapy for pancreatic cancer can be enhanced by concurrent administration of CGP75166 or C225. Therapy beginning 7 days after orthtotopic injection of IxlO6 L3.6pl human pancreatic cancer cells, produced 59%, 45%, and 85% reduction in pancreatic tumor volume in mice receiving gemcitabine, CGP74166, and combination therapy, respectively. Lymph node and liver métastases were most effectively reduced in mice receiving combination therapy. A significant survival benefit following combination therapy as compared was demonstrated by Kaplan-Meier survival curves. Similar results were obtained using C225 antibody. VEGF and IL-8 protein production was significantly lower in CGP75166 and CGP75166 plus gemcitabine-treated tumors which correlated with a significant decrease in microvessel density and an increase in apoptotic endothelial cells as visualized by fluorescent CD31/TUNEL double labeling. The data indicate that therapeutic strategies targeting EGF-R signaling have a significant antitumor effect on human L3.6pl pancreatic carcinoma growing in nude mice, which are mediated, in part, by inhibition of tumor-induced angiogenesis.