| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Cell and Tumor Biology |
Departments of 1 Cancer Biology and 2 Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas
Requests for reprints: Isaiah J. Fidler, Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Unit 173, P.O. Box 301429, Houston, TX 77230-1429. Phone: 713-792-8577; Fax: 713-792-8747; E-mail: ifidler{at}mdanderson.org.
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.
This article has been cited by other articles:
|
|
 |
|
  M Mimeault and S K Batra Recent progress on normal and malignant pancreatic stem/progenitor cell research: therapeutic implications for the treatment of type 1 or 2 diabetes mellitus and aggressive pancreatic cancer Gut, October 1, 2008; 57(10): 1456 - 1468. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Boehm, M. Sen, R. Seethala, W. E. Gooding, M. Freilino, S. M. Y. Wong, S. Wang, D. E. Johnson, and J. R. Grandis Combined Targeting of Epidermal Growth Factor Receptor, Signal Transducer and Activator of Transcription-3, and Bcl-XL Enhances Antitumor Effects in Squamous Cell Carcinoma of the Head and Neck Mol. Pharmacol., June 1, 2008; 73(6): 1632 - 1642. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Laquente, C. Lacasa, M. M. Ginesta, O. Casanovas, A. Figueras, M. Galan, I. G. Ribas, J. R. Germa, G. Capella, and F. Vinals Antiangiogenic effect of gemcitabine following metronomic administration in a pancreas cancer model Mol. Cancer Ther., March 1, 2008; 7(3): 638 - 647. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Beaudry, M. Nilsson, M. Rioth, D. Prox, D. Poon, L. Xu, P. Zweidler-Mckay, A. Ryan, J. Folkman, S. Ryeom, et al. Potent antitumor effects of ZD6474 on neuroblastoma via dual targeting of tumor cells and tumor endothelium Mol. Cancer Ther., February 1, 2008; 7(2): 418 - 424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kuwai, T. Nakamura, S.-J. Kim, T. Sasaki, Y. Kitadai, R. R. Langley, D. Fan, S. R. Hamilton, and I. J. Fidler Intratumoral Heterogeneity for Expression of Tyrosine Kinase Growth Factor Receptors in Human Colon Cancer Surgical Specimens and Orthotopic Tumors Am. J. Pathol., February 1, 2008; 172(2): 358 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Bertino, F. Piccardi, C. Porta, R. Favoni, M. Cilli, L. Mutti, and G. Gaudino Imatinib Mesylate Enhances Therapeutic Effects of Gemcitabine in Human Malignant Mesothelioma Xenografts Clin. Cancer Res., January 15, 2008; 14(2): 541 - 548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Normanno and A. De Luca Erlotinib in Pancreatic Cancer: Are Tumor Cells the (only) Target? J. Clin. Oncol., December 20, 2007; 25(36): 5836 - 5837. [Full Text] [PDF]
|
|
|
|
 |
|
 D. B. Hoelzinger, T. Demuth, and M. E. Berens Autocrine Factors That Sustain Glioma Invasion and Paracrine Biology in the Brain Microenvironment J Natl Cancer Inst, November 7, 2007; 99(21): 1583 - 1593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Shimamura, R. E. Royal, M. Kioi, A. Nakajima, S. R. Husain, and R. K. Puri Interleukin-4 Cytotoxin Therapy Synergizes with Gemcitabine in a Mouse Model of Pancreatic Ductal Adenocarcinoma Cancer Res., October 15, 2007; 67(20): 9903 - 9912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Oehler-Janne, W. Jochum, O. Riesterer, A. Broggini-Tenzer, G. Caravatti, V. Vuong, and M. Pruschy Hypoxia modulation and radiosensitization by the novel dual EGFR and VEGFR inhibitor AEE788 in spontaneous and related allograft tumor models Mol. Cancer Ther., September 1, 2007; 6(9): 2496 - 2504. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hurtado, J. J. Lozano, E. Castellanos, L. A Lopez-Fernandez, K. Harshman, C. Martinez-A, A. R Ortiz, T. M Thomson, and R. Paciucci Activation of the epidermal growth factor signalling pathway by tissue plasminogen activator in pancreas cancer cells Gut, September 1, 2007; 56(9): 1266 - 1274. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Sennino, B. L. Falcon, D. McCauley, T. Le, T. McCauley, J. C. Kurz, A. Haskell, D. M. Epstein, and D. M. McDonald Sequential Loss of Tumor Vessel Pericytes and Endothelial Cells after Inhibition of Platelet-Derived Growth Factor B by Selective Aptamer AX102 Cancer Res., August 1, 2007; 67(15): 7358 - 7367. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Bertino, C. Porta, D. Barbone, S. Germano, S. Busacca, S. Pinato, G. Tassi, R. Favoni, G. Gaudino, and L. Mutti Preliminary data suggestive of a novel translational approach to mesothelioma treatment: imatinib mesylate with gemcitabine or pemetrexed Thorax, August 1, 2007; 62(8): 690 - 695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Lu, A. A. Kamat, Y. G. Lin, W. M. Merritt, C. N. Landen, T. J. Kim, W. Spannuth, T. Arumugam, L. Y. Han, N. B. Jennings, et al. Dual Targeting of Endothelial Cells and Pericytes in Antivascular Therapy for Ovarian Carcinoma Clin. Cancer Res., July 15, 2007; 13(14): 4209 - 4217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Ortiz-Zapater, S. Peiro, O. Roda, J. M. Corominas, S. Aguilar, C. Ampurdanes, F. X. Real, and P. Navarro Tissue Plasminogen Activator Induces Pancreatic Cancer Cell Proliferation by a Non-Catalytic Mechanism That Requires Extracellular Signal-Regulated Kinase 1/2 Activation through Epidermal Growth Factor Receptor and Annexin A2 Am. J. Pathol., May 1, 2007; 170(5): 1573 - 1584. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Baranowska-Kortylewicz, M. Abe, J. Nearman, and C. A. Enke Emerging Role of Platelet-Derived Growth Factor Receptor-{beta} Inhibition in Radioimmunotherapy of Experimental Pancreatic Cancer Clin. Cancer Res., January 1, 2007; 13(1): 299 - 306. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kitadai, T. Sasaki, T. Kuwai, T. Nakamura, C. D. Bucana, and I. J. Fidler Targeting the Expression of Platelet-Derived Growth Factor Receptor by Reactive Stroma Inhibits Growth and Metastasis of Human Colon Carcinoma Am. J. Pathol., December 1, 2006; 169(6): 2054 - 2065. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Bianco, E. Giovannetti, F. Ciardiello, V. Mey, S. Nannizzi, G. Tortora, T. Troiani, F. Pasqualetti, G. Eckhardt, M. de Liguoro, et al. Synergistic Antitumor Activity of ZD6474, An Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, with Gemcitabine and Ionizing Radiation against Pancreatic Cancer Clin. Cancer Res., December 1, 2006; 12(23): 7099 - 7107. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Mimeault and S. K. Batra Concise Review: Recent Advances on the Significance of Stem Cells in Tissue Regeneration and Cancer Therapies Stem Cells, November 1, 2006; 24(11): 2319 - 2345. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Giroux, J. Iovanna, and J.-C. Dagorn Probing the human kinome for kinases involved in pancreatic cancer cell survival and gemcitabine resistance FASEB J, October 1, 2006; 20(12): 1982 - 1991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Summy and G. E. Gallick Treatment for Advanced Tumors: Src Reclaims Center Stage Clin. Cancer Res., March 1, 2006; 12(5): 1398 - 1401. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
