Sequence-dependent effects of ZD1839 (‘Iressa’) in combination with cytotoxic treatment in human head and neck cancer

Abstract

Elevated levels of epidermal growth factor receptor in head and neck cancer have been extensively reported, and are correlated with poor prognosis. The combination of cisplatin and 5-fluorouracil is a standard treatment regimen for head and neck cancer, with radiation representing another therapeutic option. Six head and neck cancer cell lines were used to study the cytotoxic effects of combining ZD1839 ('Iressa'), a new selective epidermal growth factor receptor tyrosine kinase inhibitor, and radiation. Two of the cell lines were also used to study the combination of ZD1839 and cisplatin/5-fluorouracil. Cytotoxic effects were assessed by the MTT test. The results indicated that ZD1839 applied before radiation gave the best effects (P=0.002); an effect that was strongest in those p53-mutated cell lines that express the highest epidermal growth factor receptor levels. The effects of ZD1839 with cisplatin and/or 5-fluorouracil were sequence dependent (P50

Molecular mechanisms underlying the interaction between ZD1839 (‘Iressa’) and cisplatin/5-fluorouracil

“…The cytotoxic effects resulting from this drug combination were analysed as described previously (Magné et al, 2002a). A mean combination index (according to Chou and Talalay, 1984) of 0.4 was found, which confirmed the existence of the previously reported synergistic cytotoxic activity (Magné et al, 2002a).…”

“…Similar enhancement of activity has also been observed in studies combining EGFR-targeting agents, particularly the monoclonal antibody IMC C225 (cetuximab), with ionizing radiation (Huang et al, 1999;Saleh et al, 1999;Bianco et al, 2000;Bonner et al, 2000;Milas et al, 2000). Other investigators (Williams et al, 2002) and this laboratory (Magné et al, 2002a) recently showed supra-additive effects between irradiation and ZD1839, confirming the radiosensitisation conferred by an EGFRtargeting agent. We also reported a synergistic interaction between ZD1839 and the cisplatin -5FU combination (Magné et al, 2002a).…”

“…Other investigators (Williams et al, 2002) and this laboratory (Magné et al, 2002a) recently showed supra-additive effects between irradiation and ZD1839, confirming the radiosensitisation conferred by an EGFRtargeting agent. We also reported a synergistic interaction between ZD1839 and the cisplatin -5FU combination (Magné et al, 2002a). This synergistic cytotoxicity observed in vitro in the head and neck human cancer cell line CAL33 was strictly dependent on the order of combination, with optimum effects observed when ZD1839 was applied before and during cisplatin -5FU treatment.…”

“…These conditions are comparable to 3000 cells per well in 96-well microtitration plates, as used in the previously published study (Magné et al, 2002a).…”

“…The human head and neck cancer cell line CAL33 was used in the present study as in our previous work (Magné et al, 2002a). CAL33 cells carry a p53 mutation (codon 175: CGC-CAC) and exhibit high EGFR expression (34 000 fmol mg À1 protein).…”