Elsevier

Neoplasia

Volume 7, Issue 7, July 2005, Pages 696-704
Neoplasia

Induction of Apoptosis in Tumor-Associated Endothelial Cells and Therapy of Orthotopic Human Pancreatic Carcinoma in Nude Mice1

https://doi.org/10.1593/neo.05193Get rights and content
Under a Creative Commons license
open access

Abstract

Although gemcitabine has been accepted as the firstline chemotherapeutic reagent for advanced pancreatic cancer, improvement of response rate and survival is not sufficient and patients often develop resistance. We hypothesized that the inhibition of phosphorylation of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) on tumor cells and tumor-associated endothelial cells, combined with gemcitabine, would overcome the resistance to gemcitabine in orthotopic pancreatic tumor animal model. L3.6pl, human pancreatic cancer cells growing in the pancreas, tumor-associated endothelial cells in microorgan environment highly expressed phosphorylated EGFR, VEGFR, AM, which regulates antiapoptotic mechanism. Oral administration of AEE788 (dual tyrosine kinase inhibitor against EGFR and VEGFR) inhibited the phosphorylation of EGFR, VEGFR, AM on tumor-associated endothelial cells as well as tumor cells. Although intraperitoneal (i.p.) injection of gemcitabine showed limited inhibitory effect on tumor growth, combination with AEE788 and gemcitabine produced nearly 95% inhibition of tumor growth in parallel with a high level of apoptosis on tumor cells and tumor-associated endothelial cells, decreased microvascular density and proliferation rate. Collectively, these data indicate that dual inhibition of phosphorylation of EGFR and VEGFR, in combination with gemcitabine, produces apoptosis of tumor-associated endothelial cells and significantly suppresses human pancreatic cancer in nude mice.

Keywords

AEE788
EGFR
VEGFR
gemcitabine
pancreatic cancer

Abbreviations

EGFR
epidermal growth factor receptor
HBSS
Hanks' balanced salt solution
VEGFR
vascular endothelial growth factor receptor
MVD
microvascular density
PBS
phosphate-buffered saline
PCNA
proliferating cell nuclear antigen

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1

This work was supported, in part, by Cancer Center Support grant CA16672, SPORE in Prostate Cancer grant CA90270, SPORE in Pancreatic Cancer grant CA10193-06 from the National Cancer Institute, National Institutes of Health, by a sponsored research agreement from Novartis Pharma (Basel, Switzerland). S. R. Hamilton is the recipient of the Frederick F. Becker Distinguished University Chair in Cancer Research from The University of Texas.