title: Inhibition of EGFR phosphorylation in a panel of human breast cancer cells correlates with synergistic interactions between gefitinib and 5'-DFUR, the bioactive metabolite of Xeloda.
abstract: Capecitabine (Xeloda) is a prodrug of 5-FU used in the clinical management of advanced breast cancer. It is metabolized first in the liver by carboxylesterases to generate 5'-deoxy-5-flurocytidine ribose (5'-DFCR), which is subsequently converted to 5'-deoxy-5-fluorouridine ribose (5'-DFUR) by cytidine deaminase in tumour and normal tissues. The conversion of 5'-DFUR to the cytotoxic 5-FU, occurs primarily in the tumour and is catalyzed by thymidine phosphorylase (TP). Prior work in head and neck cancer showed that cell treatment with an inhibitor of the epidermal growth receptor (EGFR) gefitinib led to an increase in TP expression and sensitized them to 5'-DFUR. This work seeks to investigate the factors influencing the potency of gefitinib + 5'-DFUR combination. Here, we studied these factors in a panel of six human breast cancer cell lines, with varied levels of sensitivity to gefitinib. Our results first confirmed that 5'-DFUR potency linearly correlates with TP basal levels in the panel of cell lines. In contrast, the strength of the synergistic effect of the gefitinib + 5'-DFUR combination, as measured by their combination indices (CI) correlates with pEGFR percent inhibition and with the modulation of TP expression by gefitinib (as quantitated by TP fold change) rather than TP basal levels. The results, in toto, suggest that the extent of modulation of TP by gefitinib may be used as a predictor of tumour sensitivity to gefitinib + capecitabine/5'-DFUR combinations.
authors.affiliation: Cancer Drug Research Laboratory, Department of Medicine, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West, Montreal, QC H3A 1A1, Canada.
authors.forename: Maria
authors.initials: M
authors.lastname: Ait-Tihyaty
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Rachid
authors.forename: Catalin
authors.initials: C
authors.lastname: Mihalcioiu
authors.forename: Bertrand J
authors.initials: BJ
authors.lastname: Jean-Claude
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms; D000069287:Capecitabine; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005467:Floxuridine / Q000494:pharmacology*; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077156:Gefitinib; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008727:Methotrexate / Q000494:pharmacology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011799:Quinazolines / Q000494:pharmacology*; D013939:Thymidine Phosphorylase / Q000235:genetics / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D005467:Floxuridine; D003841:Deoxycytidine; D000069287:Capecitabine; D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; D066246:ErbB Receptors; D000077156:Gefitinib; D005472:Fluorouracil; C025034:doxifluridine; D008727:Methotrexate