Sequence dependence of cell growth inhibition by EGFR-tyrosine kinase inhibitor ZD1839, docetaxel, and cisplatin in head and neck cancer.
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.


CONCLUSIONS
These data suggests that it is feasible to design clinical trials with these settings to maximize the efficacy of this combined drug regimen.
Klass
Carmen M
CM
Department of Hematology and Medical Oncology, Winship Cancer Institute, Atlanta, Georgia 30322, USA.
Choe
Mi Sun
MS
Hurwitz
Selwyn J
SJ
Tighiouart
Mourad
M
Zhang
Xin
X
Chen
Zhuo Georgia
ZG
Shin
Dong M
DM
D017304:Annexin A5 / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000077156:Gefitinib; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000493:pharmacokinetics* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured
D017304:Annexin A5; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D043823:Taxoids; D000077143:Docetaxel; D066246:ErbB Receptors; D002945:Cisplatin; D000077156:Gefitinib