Molecular mechanisms underlying the interaction between ZD1839 (|[lsquo]|Iressa|[rsquo]|) and cisplatin|[sol]|5-fluorouracil

摘要

ZD1839 (‘Iressa’), an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is currently being investigated in clinical trials as a treatment for cancer. ‘Iressa’ is a trademark of the AstraZeneca group of companies. We have previously demonstrated a synergistic interaction between ZD1839 and cisplatin/5-fluorouracil (5FU) in CAL33, a human head and neck cancer cell line that markedly expresses EGFR. This study examined the effects of this drug combination on the cell cycle, cell cycle regulators, apoptosis-related factors, EGFR-related signalling and DNA repair in CAL33 cells. The cells were incubated with ZD1839 alone for 48?h, then cisplatin and 5FU were added. Exposure to the drug combination continued for a further 48?h. ZD1839 alone induced accumulation of cells in the G0/G1 phase of the cell cycle at 24?h accompanied by a concomitant increase in p21, p27 and Bax, a significant decrease in Bcl2 and a decrease in Akt phosphorylation. A decrease in DNA-PK was observed at 48?h. ZD1839 alone had no effect on caspase-3 activity, but addition of ZD1839 to cisplatin-5FU led to a significant increase in caspase-3 activity at 96?h. Thus, ZD1839 affects key cellular pathways controlling cell proliferation, apoptosis and DNA repair. These data provide a rationale to support clinical trials combining ZD1839 and cisplatin–5FU and other protocols that combine EGFR-targeting agents with chemotherapy or radiotherapy.