SEQUENCE DEPENDENCE OF CELL GROWTH INHIBITION BY EGFR–TYROSINE KINASE INHIBITOR ZD1839, DOCETAXEL, AND CISPLATIN IN HEAD AND NECK CANCER

Abstract

Background. This study was to explore whether the efficacy of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Z, Iressa, gefitinib) plus chemotherapeutic agents docetaxel (D) and cisplatin (P) may benefit from sequencing of the combination. Methods. Three head and neck cancer cell lines were used to study the effect of various combinations of and relative sequencing of D, P, and Z in cell growth inhibition. A popula- tion pharmacokinetic stimulation study was conducted on Z in silico and used together with the growth inhibition data to derive principles for future in vivo use of this drug combination. Results. The inhibitory effects of Z on combinations of D and P were sequence dependent. Treatment simultaneously with DPZ or with DP followed by Z (DP!Z) showed synergistic effects in all 3 cell lines. However, sequencing with Z followed by DP (Z!DP), gave an antagonistic effect, suggesting that D and P should be administered when the effect of Z is low. The induction of apoptosis was also sequence dependent. The in silico pharmacokinetic study suggested the feasibility of deriv- ing a 5-day-on/2-day-off regimen for Z, in which D and P administration commences when levels of Z are low, allowing levels of Z to accumulate sufficiently during the remainder of the cycle. Conclusion. These data suggests that it is feasible to design clinical trials with these settings to maximize the effi- cacy of this combined drug regimen. V V C 2009 Wiley Periodi- cals, Inc. Head Neck 31: 1263–1273, 2009 Keywords: EGFR; cytotoxic agent; docetaxel; cisplatin; apoptosis; head and neck cancer