TY - JOUR
T1 - Induction of apoptosis in tumor-associated endothelial cells and therapy of orthotopic human pancreatic carcinoma in nude mice
AU - Yokoi, Kenji
AU - Kim, Sun Jin
AU - Thaker, Premal
AU - Yazici, Sertac
AU - Nam, Do Hyun
AU - He, Junqin
AU - Sasaki, Takamitsu
AU - Chiao, Paul J.
AU - Sclabas, Guido M.
AU - Abbruzzese, James L.
AU - Hamilton, Stanley R.
AU - Fidler, Isaiah J.
N1 - Funding Information:
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 Address all correspondence to: Isaiah J. Fidler, Department of Cancer Biology, Unit 173, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail: [email protected] 1This work was supported, in part, by Cancer Center Support grant CA16672, SPORE in Prostate Cancer grant CA90270, and SPORE in Pancreatic Cancer grant CA10193-06 from the National Cancer Institute, National Institutes of Health, and 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. Received 21 February 2005; Revised 1 April 2005; Accepted 5 April 2005.
PY - 2005/7
Y1 - 2005/7
N2 - Although gemcitabine has been accepted as the first-line 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, and tumor-associated endothelial cells in microorgan environment highly expressed phosphorylated EGFR, VEGFR, and Akt, which regulates antiapoptotic mechanism. Oral administration of AEE788 (dual tyrosine kinase inhibitor against EGFR and VEGFR) inhibited the phosphorylation of EGFR, VEGFR, and Akt 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, and 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.
AB - Although gemcitabine has been accepted as the first-line 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, and tumor-associated endothelial cells in microorgan environment highly expressed phosphorylated EGFR, VEGFR, and Akt, which regulates antiapoptotic mechanism. Oral administration of AEE788 (dual tyrosine kinase inhibitor against EGFR and VEGFR) inhibited the phosphorylation of EGFR, VEGFR, and Akt 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, and 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.
KW - AEE788
KW - EGFR
KW - Gemcitabine
KW - Pancreatic cancer
KW - VEGFR
UR - http://www.scopus.com/inward/record.url?scp=23244462565&partnerID=8YFLogxK
U2 - 10.1593/neo.05193
DO - 10.1593/neo.05193
M3 - Article
C2 - 16026649
AN - SCOPUS:23244462565
SN - 1522-8002
VL - 7
SP - 696
EP - 704
JO - Neoplasia
JF - Neoplasia
IS - 7
ER -