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Sequence dependence of cell growth inhibition by EGFR–tyrosine kinase inhibitor ZD1839, docetaxel, and cisplatin in head and neck cancer
Author(s) -
Klass Carmen M.,
Choe Mi Sun,
Hurwitz Selwyn J.,
Tighiouart Mourad,
Zhang Xin,
Chen Zhuo Georgia,
Shin Dong M.
Publication year - 2009
Publication title -
head and neck
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.012
H-Index - 127
eISSN - 1097-0347
pISSN - 1043-3074
DOI - 10.1002/hed.21103
Subject(s) - docetaxel , gefitinib , pharmacology , tyrosine kinase inhibitor , cisplatin , regimen , medicine , growth inhibition , in vivo , pharmacokinetics , oncology , head and neck cancer , population , tyrosine kinase , in silico , epidermal growth factor receptor , cancer research , cancer , cell growth , biology , chemotherapy , receptor , biochemistry , microbiology and biotechnology , environmental health , gene
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 population 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 deriving 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 efficacy of this combined drug regimen. © 2009 Wiley Periodicals, Inc. Head Neck, 2009