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

C. J. Bruns, S. Ozawa, M. T. Harbison, V. Tsan, C. C. Solorzano, David McConkey, R. Radinsky, A. H. Kölscher, I. J. Fidler

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)386
Number of pages1
JournalLangenbeck's Archives of Surgery
Volume386
Issue number5
Publication statusPublished - 2001
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Surgery

Cite this