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Induction of apoptosis in tumor-associated endothelial cells and therapy of orthotopic human pancreatic carcinoma in nude mice.

Publication ,  Journal Article
Yokoi, K; Kim, S-J; Thaker, P; Yazici, S; Nam, D-H; He, J; Sasaki, T; Chiao, PJ; Sclabas, GM; Abbruzzese, JL; Hamilton, SR; Fidler, IJ
Published in: Neoplasia
July 2005

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.

Duke Scholars

Published In

Neoplasia

DOI

ISSN

1522-8002

Publication Date

July 2005

Volume

7

Issue

7

Start / End Page

696 / 704

Location

United States

Related Subject Headings

  • Receptors, Vascular Endothelial Growth Factor
  • Purines
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Phosphorylation
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
  • Neoplasm Transplantation
 

Citation

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Yokoi, K., Kim, S.-J., Thaker, P., Yazici, S., Nam, D.-H., He, J., … Fidler, I. J. (2005). Induction of apoptosis in tumor-associated endothelial cells and therapy of orthotopic human pancreatic carcinoma in nude mice. Neoplasia, 7(7), 696–704. https://doi.org/10.1593/neo.05193
Yokoi, Kenji, Sun-Jin Kim, Premal Thaker, Sertac Yazici, Do-Hyun Nam, Junqin He, Takamitsu Sasaki, et al. “Induction of apoptosis in tumor-associated endothelial cells and therapy of orthotopic human pancreatic carcinoma in nude mice.Neoplasia 7, no. 7 (July 2005): 696–704. https://doi.org/10.1593/neo.05193.
Yokoi K, Kim S-J, Thaker P, Yazici S, Nam D-H, He J, et al. Induction of apoptosis in tumor-associated endothelial cells and therapy of orthotopic human pancreatic carcinoma in nude mice. Neoplasia. 2005 Jul;7(7):696–704.
Yokoi, Kenji, et al. “Induction of apoptosis in tumor-associated endothelial cells and therapy of orthotopic human pancreatic carcinoma in nude mice.Neoplasia, vol. 7, no. 7, July 2005, pp. 696–704. Pubmed, doi:10.1593/neo.05193.
Yokoi K, Kim S-J, Thaker P, Yazici S, Nam D-H, He J, Sasaki T, Chiao PJ, Sclabas GM, Abbruzzese JL, Hamilton SR, Fidler IJ. Induction of apoptosis in tumor-associated endothelial cells and therapy of orthotopic human pancreatic carcinoma in nude mice. Neoplasia. 2005 Jul;7(7):696–704.
Journal cover image

Published In

Neoplasia

DOI

ISSN

1522-8002

Publication Date

July 2005

Volume

7

Issue

7

Start / End Page

696 / 704

Location

United States

Related Subject Headings

  • Receptors, Vascular Endothelial Growth Factor
  • Purines
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Phosphorylation
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
  • Neoplasm Transplantation