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

✍ Scribed by Carmen M. Klass; Mi Sun Choe; Selwyn J. Hurwitz; Mourad Tighiouart; Xin Zhang; Zhuo (Georgia) Chen; Dong M. Shin

Publisher: John Wiley and Sons
Year: 2009
Tongue: English
Weight: 393 KB
Volume: 31
Category: Article
ISSN: 1043-3074
DOI: 10.1002/hed.21103

No coin nor oath required. For personal study only.

✦ Synopsis

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 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

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