title: Induction of apoptosis in tumor-associated endothelial cells and therapy of orthotopic human pancreatic carcinoma in nude mice.
abstract: 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.
authors: Department of Cancer Biology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
authors: Kenji
authors: K
authors: Yokoi
authors: Sun-Jin
authors: SJ
authors: Kim
authors: Premal
authors: P
authors: Thaker
authors: Sertac
authors: S
authors: Yazici
authors: Do-Hyun
authors: DH
authors: Nam
authors: Junqin
authors: J
authors: He
authors: Takamitsu
authors: T
authors: Sasaki
authors: Paul J
authors: PJ
authors: Chiao
authors: Guido M
authors: GM
authors: Sclabas
authors: James L
authors: JL
authors: Abbruzzese
authors: Stanley R
authors: SR
authors: Hamilton
authors: Isaiah J
authors: IJ
authors: Fidler
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D042783:Endothelial Cells / Q000473:pathology*; D066246:ErbB Receptors / Q000378:metabolism; D005091:Exons; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000628:therapy*; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011687:Purines / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011518:Proto-Oncogene Proteins; D011687:Purines; D003841:Deoxycytidine; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C489254:AEE 788; D000093542:Gemcitabine