title: Combination of the EGFR tyrosine kinase inhibitor AG1478 and 5-FU: no synergistic effect on EGFR phosphorylation, cell proliferation and apoptosis induction.
abstract: The combination of a fluoropyrimidine with receptor tyrosine kinase inhibitors in tumor treatment has been proposed to enhance their therapeutic efficiency. The synergism of such a combination in the treatment of colorectal carcinoma is equivocal although the epidermal growth factor receptor (EGFR) is frequently overexpressed in the tumors. We used human colorectal SW 480 cells, to analyze the EGFR phosphorylation levels. We showed that incubation of cells with 5-fluorouracil (5-FU) does not influence EGFR phosphorylation of tyrosine 1173 and the overall phosphorylation after stimulation. Inhibition of EGFR phosphorylation with AG1478 reduced cell proliferation compared to 5-FU. Cells exhibited highest apoptosis rates with 5-FU. AG1479 inhibited cell proliferation more potently than 5-FU alone. Apoptosis rates after incubation with AG1478 alone and AG1478 in combination with 5-FU were significantly lower than apoptosis induction by 5-FU alone. Therefore, no synergism of both substances can be demonstrated. This experimental data argues against the combination of EGFR-inhibitors with 5-FU in a clinical setting.
authors.affiliation: Clinic for Vascular and Endovascular Surgery, University Hospital Frankfurt, Germany. Michael.keese@kgu.de.
authors.forename: Vugar
authors.initials: V
authors.lastname: Yagublu
authors.forename: Zhala
authors.initials: Z
authors.lastname: Ahmadova
authors.forename: Yegana
authors.initials: Y
authors.lastname: Hajiyeva
authors.forename: Mathias
authors.initials: M
authors.lastname: Hafner
authors.forename: Michael
authors.initials: M
authors.lastname: Keese
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism*; D005434:Flow Cytometry; D031541:Fluorescence Resonance Energy Transfer; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D010766:Phosphorylation; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D020032:Tyrphostins / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors; D005472:Fluorouracil
keywords: Colorectal carcinoma; EGFR phosphorylation; SW 480 cells; chemotherapy