Antagonism between gefitinib and cisplatin in non-small cell lung cancer cells

Why randomized trials failed?

Chun Ming Tsai, Jen-Ting (Tina) Chen, David J. Stewart, Chao Hua Chiu, Chun Liang Lai, Shih Yin Hsiao, Yuh Min Chen, Kuo Ting Chang

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Introduction: Four phase III randomized trials adding epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors to standard chemotherapeutics in patients with advanced non-small cell lung cancer (NSCLC) have failed to show benefits. The mechanism of these failures was examined. Methods: Fifteen previously untreated NSCLC cell lines were simultaneously treated with gefitinib plus cisplatin. Three exhibited sensitizing-EGFR mutations. Three selected lines were further tested with paclitaxel/cisplatin, paclitaxel/gefitinib, and paclitaxel/cisplatin/gefitinib combinations. The tetrazolium colorimetric assay with application of the classic isobole method was used, and dose-versus-log-response curves (DRCs) were analyzed to evaluate possible resistance mechanisms. Results: Of the 15 cell lines tested, combined gefitinib/cisplatin was significantly antagonistic in 10 wild-type and three sensitizing-EGFR mutant cell lines (group mean combination index = 1.184, 95% confidence interval = 1.12-1.24, p = 0.001). The mean combination index values of paclitaxel/cisplatin/gefitinib were higher than or comparable with those of paclitaxel/cisplatin and paclitaxel/gefitinib. DRC analysis consistently showed nonsaturable passive resistance, suggesting that gefitinib at 0.001 to 0.3 μM can interfere with cisplatin cell entry (at concentrations >1-3 μM) in a dose-dependent manner and lead to antagonism. This antagonism may or may not be schedule dependent in different cell lines. Conclusions: In most EGFR wild-type or sensitizing-mutant NSCLC cells, the concomitant gefitinib/cisplatin combination showed antagonism, likely because gefitinib interfered with cisplatin entry into the cell. The findings that three-drug combination was not better than the two-drug combinations are in accordance with the results of the randomized trials. The EGFR-tyrosine kinase inhibitor/platinum antagonism is a possible reason for the failure of those randomized trials.

Original languageEnglish (US)
Pages (from-to)559-568
Number of pages10
JournalJournal of Thoracic Oncology
Volume6
Issue number3
DOIs
StatePublished - Mar 2011
Externally publishedYes

Fingerprint

Non-Small Cell Lung Carcinoma
Cisplatin
Epidermal Growth Factor Receptor
Cell Line
Drug Combinations
Paclitaxel
Protein-Tyrosine Kinases
gefitinib
Platinum
Appointments and Schedules
Confidence Intervals
Mutation
TP protocol

Keywords

  • Antagonism
  • Cisplatin
  • Gefitinib
  • Non-small cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Antagonism between gefitinib and cisplatin in non-small cell lung cancer cells : Why randomized trials failed? / Tsai, Chun Ming; Chen, Jen-Ting (Tina); Stewart, David J.; Chiu, Chao Hua; Lai, Chun Liang; Hsiao, Shih Yin; Chen, Yuh Min; Chang, Kuo Ting.

In: Journal of Thoracic Oncology, Vol. 6, No. 3, 03.2011, p. 559-568.

Research output: Contribution to journalArticle

Tsai, Chun Ming ; Chen, Jen-Ting (Tina) ; Stewart, David J. ; Chiu, Chao Hua ; Lai, Chun Liang ; Hsiao, Shih Yin ; Chen, Yuh Min ; Chang, Kuo Ting. / Antagonism between gefitinib and cisplatin in non-small cell lung cancer cells : Why randomized trials failed?. In: Journal of Thoracic Oncology. 2011 ; Vol. 6, No. 3. pp. 559-568.
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