Antivascular Therapy of Human Follicular Thyroid Cancer Experimental Bone Metastasis by Blockade of Epidermal Growth Factor Receptor and Vascular Growth Factor Receptor Phosphorylation
| Autor: | Benjamin N. Bekele, Isaiah J. Fidler, Mahitosh Mandal, Yasemin D. Yazici, Samar A. Jasser, Sun Jin Kim, Valerie S. Hawthorne, Young Wook Park, Corazon D. Bucana, Maher N. Younes, Jeffrey N. Myers, Orhan G. Yigitbasi |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Male
Cancer Research Paclitaxel medicine.drug_class Mice Nude Apoptosis Bone Neoplasms Protein Serine-Threonine Kinases Polymerase Chain Reaction Tyrosine-kinase inhibitor Mice Growth factor receptor Proto-Oncogene Proteins Adenocarcinoma Follicular Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans Thyroid Neoplasms AEE788 Epidermal growth factor receptor Phosphorylation Follicular thyroid cancer Protein kinase B Cell Proliferation Neovascularization Pathologic biology business.industry Bone metastasis Drug Synergism Kinase insert domain receptor medicine.disease Vascular Endothelial Growth Factor Receptor-2 ErbB Receptors Receptors Vascular Endothelial Growth Factor Oncology Purines Cancer research biology.protein Mitogen-Activated Protein Kinases business Proto-Oncogene Proteins c-akt |
| Zdroj: | Cancer Research. 65:4716-4727 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Patients suffering from bone metastases of follicular thyroid carcinoma (FTC) have a poor prognosis because of the lack of effective treatment strategies. The overexpression of epidermal growth factor receptor (EGFR) associated with increased vascularity has been implicated in the pathogenesis of FTC and subsequent bone metastases. We hypothesized that inhibiting the phosphorylation of the EGFR and vascular endothelial growth factor receptor (VEGFR) by AEE788, a dual tyrosine kinase inhibitor of EGFR and VEGFR, in combination with paclitaxel would inhibit experimental FTC bone lesions and preserve bone structure. We tested this hypothesis using the human WRO FTC cell line. In culture, AEE788 inhibited the EGF-mediated phosphorylation of EGFR, VEGFR2, mitogen-activated protein kinase, and Akt in culture. AEE788, alone and in combination with paclitaxel, inhibited cell growth and induced apoptosis. When WRO cells were injected into the tibia of nude mice, tumor and endothelial cells within the lesions expressed phosphorylated EGFR, VEGFR, Akt, and mitogen-activated protein kinase that were inhibited by the oral administration of AEE788. Therapy consisting of orally given AEE788 and i.p. injected paclitaxel induced a high level of apoptosis in tumor-associated endothelial cells and tumor cells with the inhibition of tumor growth in the bone and the preservation of bone structure. Collectively, these data show that blocking the phosphorylation of EGFR and VEGFR with AEE788 combined with paclitaxel can significantly inhibit experimental human FTC in the bone of nude mice. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|