The Sequence Dependence of Cell Growth Inhibition by EGFR-Tyrosine Kinase Inhibitor ZD1839, Docetaxel and Cisplatin in Head and Neck Cancer

• Type of Material: Article
• Authors: Carmen M. Klass, Emory University; Mi Sun Choe, Emory University; Selwyn Hurwitz, Emory University; Mourad Tighiouart, Emory University; Xin Zhang, Emory University; Georgia Chen, Emory University; Dong M Shin, Emory University
• Language: English
• Date: 2009-10
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 Wiley Periodicals, Inc.
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1002/hed.21103/abstract
• Title of Journal or Parent Work: Head and Neck
• ISSN: 1043-3074
• Volume: 31
• Issue: 10
• Start Page: 1263
• End Page: 1273
• Grant/Funding Information: This study was supported by NCI P50 CA128613, RO1 CA112643, and U01 101244 grant (D.M.S.), and Georgia Cancer Coalition Distinguished Scholar (D.M.S. and Z.C.).
• Keywords: cisplatin; docetaxel; cytotoxic agent; EGFR; apoptosis; head and neck cancer
• Research Categories: Health Sciences, Oncology

Abstract

Background This study was to explore whether the efficacy of the 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 to 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 three 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.