Erlotinib in Combination with Capecitabine (5'dFUR) in Resistant Pancreatic Cancer Cell Lines
| Autor: | H. Marouani, J. L. Fischel, P. Formento, N. Renée, M. Chefrour, G. Milano, C. Mercier, Mireille Francoual, J. Ciccolini, R.-M. Ferri-Dessens, S. Giacometti |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Vascular Endothelial Growth Factor A
Antimetabolites Antineoplastic medicine.medical_specialty medicine.drug_class Biology Deoxycytidine Tyrosine-kinase inhibitor Capecitabine Erlotinib Hydrochloride Cell Line Tumor Pancreatic cancer Internal medicine medicine Dihydropyrimidine dehydrogenase Humans Drug Interactions Pharmacology (medical) Thymidine phosphorylase Protein Kinase Inhibitors Dihydrouracil Dehydrogenase (NADP) Cell Proliferation Pharmacology Thymidine Phosphorylase Cancer medicine.disease ErbB Receptors Pancreatic Neoplasms Infectious Diseases Endocrinology Oncology Drug Resistance Neoplasm Quinazolines Cancer research Fluorouracil Erlotinib medicine.drug |
| Zdroj: | Journal of Chemotherapy. 22:129-133 |
| ISSN: | 1973-9478 1120-009X |
| DOI: | 10.1179/joc.2010.22.2.129 |
| Popis: | The combination of capecitabine and the tyrosine kinase inhibitor erlotinib has recently been tested in patients with gemcitabine-refractory pancreatic tumors, with limited success. To understand this lack of efficacy, we studied the molecular effects of these agents in Capan-1 and Capan-2 human pancreatic resistant cancer cells. Erlotinib up-regulated thymidine phosphorylase (+50%) and downregulated dihydropyrimidine dehydrogenase (+55%) in a cell-dependent manner, thus suggesting that the combination should result in synergism. However, only mild additivity was achieved at best when combining both drugs, and several sequences tested even led to strong antagonism. Further experiments were performed to understand this lack of efficacy. We found that the fluoropyrimidine down-regulated EGFR expression by 30%, an unexpected finding resulting in a possible reduction in efficacy when cells were subsequently exposed to erlotinib. We also observed marked drug-induced over-expression of both cytosolic and extracellular vascular endothelial growth factor (VEGF) secretion, thus possibly triggering proliferation. These preliminary findings strongly suggest that these observations could be new mechanisms in the development of acquired drug resistance in pancreatic cancer cells. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|