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
| العنوان: | 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 |
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| المؤلفون: | Giampaolo Tortora, Elisa Giovannetti, Mario Del Tacca, David Raben, Francesco Pasqualetti, Fortunato Ciardiello, Cataldo Bianco, S. Ricciardi, Teresa Troiani, Luca Cionini, Valentina Mey, Gail Eckhardt, Mario De Liguoro, Romano Danesi, Sara Nannizzi |
| المساهمون: | Bianco, C, Giovannetti, E, Ciardiello, F, Mey, V, Nannizzi, S, Tortora, Giampaolo, Troiani, T, Pasqualetti, F, Eckhardt, G, DE LIGUORO, M, Ricciardi, S, DEL TACCA, M, Raben, D, Cionini, L, Danesi, R., Ciardiello, Fortunato, Tortora, G, Troiani, Teresa, de Liguoro, M, Del Tacca, M, Medical oncology laboratory, AGEM - Re-generation and cancer of the digestive system, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, CCA - Cancer Treatment and quality of life, AII - Cancer immunology |
| المصدر: | Bianco, C, Giovannetti, E, Ciardiello, F, Mey, V, Nannizzi, S, Tortora, G, Troiani, T, Pasqualetti, F, Eckhardt, G, De Liguoro, M, Ricciardi, S, Del Tacca, M, Raben, D, Cionini, L & Danesi, R 2006, ' 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 ', Clinical Cancer Research, vol. 12, no. 23, pp. 7099-7107 . https://doi.org/10.1158/1078-0432.CCR-06-0833Test Clinical Cancer Research, 12(23), 7099-7107. American Association for Cancer Research Inc. |
| بيانات النشر: | American Association for Cancer Research (AACR), 2006. |
| سنة النشر: | 2006 |
| مصطلحات موضوعية: | Cancer Research, endocrine system diseases, Angiogenesis, Apoptosis, Deoxycytidine, Polymerase Chain Reaction, ZD6474, Mice, chemistry.chemical_compound, Piperidines, Radiation, Ionizing, Antineoplastic Combined Chemotherapy Protocols, Growth factor receptor inhibitor, Epidermal growth factor receptor, Phosphorylation, Cell Cycle, gemcitabine, Drug Synergism, Combined Modality Therapy, ErbB Receptors, Vascular endothelial growth factor, Oncology, Female, Tyrosine kinase, Signal Transduction, medicine.drug, EGFR, Transplantation, Heterologous, Mice, Nude, Biology, pancreas cancer, Growth factor receptor, Predictive Value of Tests, Cell Line, Tumor, Deoxycytidine Kinase, medicine, Animals, Humans, Protein kinase B, Cell Proliferation, Gene Expression Profiling, Dose-Response Relationship, Radiation, Gemcitabine, Pancreatic Neoplasms, Disease Models, Animal, Receptors, Vascular Endothelial Growth Factor, chemistry, Quinazolines, Cancer research, biology.protein, Drug Screening Assays, Antitumor |
| الوصف: | Purpose: Standard treatments have modest effect against pancreatic cancer, and current research focuses on agents targeting molecular pathways involved in tumor growth and angiogenesis. This study investigated the interactions between ZD6474, an inhibitor of tyrosine kinase activities of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor (EGFR), gemcitabine, and ionizing radiation in human pancreatic cancer cells and analyzed the molecular mechanisms underlying this combination.Experimental Design: ZD6474, ionizing radiation, and gemcitabine, alone or in combination, were given in vitro to MIA PaCa-2, PANC-1, and Capan-1 cells and in vivo to MIA PaCa-2 tumor xenografts. The effects of treatments were studied by the evaluation of cytotoxicity, apoptosis, cell cycle, EGFR and Akt phosphorylation, modulation of gene expression of enzymes related to gemcitabine activity (deoxycytidine kinase and ribonucleotide reductase), as well as vascular endothelial growth factor immunohistochemistry and microvessel count.Results: In vitro, ZD6474 dose dependently inhibited cell growth, induced apoptosis, and synergistically enhanced the cytotoxic activity of gemcitabine and ionizing radiation. Moreover, ZD6474 inhibited phosphorylation of EGFR and Akt and triggered cell apoptosis. PCR analysis showed that ZD6474 increased the ratio between gene expression of deoxycytidine kinase and ribonucleotide reductase. In vivo, ZD6474 showed significant antitumor activity alone and in combination with radiotherapy and gemcitabine, and the combination of all three modalities enhanced MIA PaCA-2 tumor growth inhibition compared with gemcitabine alone.Conclusions: ZD6474 decreases EGFR and Akt phosphorylation, enhances apoptosis, favorably modulates gene expression in cancer cells, and acts synergistically with gemcitabine and radiotherapy to inhibit tumor growth. These findings support the investigation of this combination in the clinical setting. |
| وصف الملف: | STAMPA |
| تدمد: | 1557-3265 1078-0432 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5030181ea65727aeeb62246e97727d51Test https://doi.org/10.1158/1078-0432.ccr-06-0833Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....5030181ea65727aeeb62246e97727d51 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573265 10780432 |
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