Simultaneous inhibition of EGFR, VEGFR, and platelet-derived growth factor receptor signaling combined with gemcitabine produces therapy of human pancreatic carcinoma and prolongs survival in an orthotopic nude mouse model.
Although gemcitabine has been approved as the first-line chemotherapeutic reagent for pancreatic cancer, its response rate is low and average survival duration is still only marginal. Because epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR) modulate tumor progression, we hypothesized that inhibition of phosphorylation of all three on tumor cells, tumor-associated endothelial cells, and stroma cells would improve the treatment efficacy of gemcitabine in an orthotopic pancreatic tumor model in nude mice and prolong survival. We implanted L3.6pl, a human pancreatic cancer cell, in the pancreas of nude mice. We found that tumor-associated endothelial cells in this model highly expressed phosphorylated EGFR, VEGFR, and PDGFR. Oral administration of AEE788, a dual tyrosine kinase inhibitor against EGFR and VEGFR, decreased phosphorylation of EGFR and VEGFR. PDGFR phosphorylation was inhibited by STI571. Although i.p. injection of gemcitabine did not inhibit tumor growth, its combination with AEE788 and STI571 produced >80% inhibition of tumor growth and prolonged survival in parallel with increases in number of tumor cells and tumor-associated endothelial cell apoptosis, decreased microvascular density, decreased proliferation rate, and prolonged survival. STI571 treatment also decreased pericyte coverage on tumor-associated endothelial cells. Thus, inhibiting phosphorylation of EGFR, VEGFR, and PDGFR in combination with gemcitabine enhanced the efficacy of gemcitabine, resulting in inhibition of experimental human pancreatic cancer growth and significant prolongation of survival.
Yokoi
Kenji
K
Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77230-1429, USA.
Sasaki
Takamitsu
T
Bucana
Corazon D
CD
Fan
Dominic
D
Baker
Cheryl H
CH
Kitadai
Yasuhiko
Y
Kuwai
Toshio
T
Abbruzzese
James L
JL
Fidler
Isaiah J
IJ
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001549:Benzamides; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D001549:Benzamides; D010879:Piperazines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011687:Purines; D011743:Pyrimidines; D003841:Deoxycytidine; D000068877:Imatinib Mesylate; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; C489254:AEE 788; D000093542:Gemcitabine