TY - JOUR
T1 - Combined epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor and chemotherapy in non-small-cell lung cancer
T2 - Chemo-refractoriness of cells harboring sensitizing-EGFR mutations in the presence of gefitinib
AU - Tsai, Chun Ming
AU - Chen, Jen Ting
AU - Chiu, Chao Hua
AU - Lai, Chun Liang
AU - Hsiao, Shih Yin
AU - Chang, Kuo Ting
N1 - Funding Information:
This study was supported, in part, by grants from the National Science Council ( NSC-98-2314-B-075-044-MY3 and NSC-100-2314-B-075-045 ); the Center of Excellence for Cancer Research at Taipei Veterans General Hospital ( DOH99-TD-C-111-007 , DOH100-TD-C-111-007 and DOH101-TD-C-111-007 ); and the Taipei Veteran General Hospital ( V98C1-030 , V99-C1-152 and V100-C1-149 ).
PY - 2013/11
Y1 - 2013/11
N2 - Background: Combined epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) with chemotherapy is believed to be more effective in treating non-small-cell lung cancer (NSCLC) with sensitizing-EGFR mutation (SEM). This hypothesis failed to be realized clinically and needs to be examined in vitro. Materials and methods: Using the tetrazolium colorimetric assay and classical isobole method, we investigated the combination effects of 6 gefitinib-chemotherapeutic doublets (gefitinib/cisplatin, gemcitabine, pemetrexed, paclitaxel, docetaxel, or vinorelbine) in a panel of 15 NSCLC cell lines. Results: Upon treatment with the 6 gefitinib-chemotherapeutic doublets, the 12 cell lines that did not harbor SEM displayed a broad spectrum of group results, from obvious synergism to robust antagonism. The values of group mean combination index (mCIs) ranged from 0.769 to 1.201. In contrast, the 3 cell lines with SEM showed a tendency toward consistent antagonism to the tested doublets, impressively, with a narrow range of higher group mCIs (0.993-1.141). In the presence of gefitinib, the SEM or gefitinib-sensitive group was more chemo-refractory than the non-SEM (index of chemo-refractoriness (RI): 69.33 versus 42.67; P= 0.036) or gefitinib-resistant group (68.25 versus 40.64, P= 0.0108), respectively. The results of using the gefitinib/drug combinations with the gefitinib-sensitive non-SEM cell line H322 and the gefitinib-resistant EGFR mutant H820 shared patterns similar to those with the SEM and non-SEM cell lines, respectively. Conclusion: Gefitinib-treated EGFR-TKI-sensitive NSCLC cells showed a wide spectrum of chemo-refractoriness, suggesting that concomitantly combined EGFR-TKI-chemotherapy might not be a good treatment strategy for NSCLC harboring SEM.
AB - Background: Combined epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) with chemotherapy is believed to be more effective in treating non-small-cell lung cancer (NSCLC) with sensitizing-EGFR mutation (SEM). This hypothesis failed to be realized clinically and needs to be examined in vitro. Materials and methods: Using the tetrazolium colorimetric assay and classical isobole method, we investigated the combination effects of 6 gefitinib-chemotherapeutic doublets (gefitinib/cisplatin, gemcitabine, pemetrexed, paclitaxel, docetaxel, or vinorelbine) in a panel of 15 NSCLC cell lines. Results: Upon treatment with the 6 gefitinib-chemotherapeutic doublets, the 12 cell lines that did not harbor SEM displayed a broad spectrum of group results, from obvious synergism to robust antagonism. The values of group mean combination index (mCIs) ranged from 0.769 to 1.201. In contrast, the 3 cell lines with SEM showed a tendency toward consistent antagonism to the tested doublets, impressively, with a narrow range of higher group mCIs (0.993-1.141). In the presence of gefitinib, the SEM or gefitinib-sensitive group was more chemo-refractory than the non-SEM (index of chemo-refractoriness (RI): 69.33 versus 42.67; P= 0.036) or gefitinib-resistant group (68.25 versus 40.64, P= 0.0108), respectively. The results of using the gefitinib/drug combinations with the gefitinib-sensitive non-SEM cell line H322 and the gefitinib-resistant EGFR mutant H820 shared patterns similar to those with the SEM and non-SEM cell lines, respectively. Conclusion: Gefitinib-treated EGFR-TKI-sensitive NSCLC cells showed a wide spectrum of chemo-refractoriness, suggesting that concomitantly combined EGFR-TKI-chemotherapy might not be a good treatment strategy for NSCLC harboring SEM.
KW - Combination therapy
KW - EGFR mutation
KW - Epidermal growth factor receptor (EGFR)
KW - Non-small-cell lung cancer (NSCLC)
KW - Tyrosine kinase inhibitor (TKI)
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U2 - 10.1016/j.lungcan.2013.08.028
DO - 10.1016/j.lungcan.2013.08.028
M3 - Article
C2 - 24055492
AN - SCOPUS:84887016439
SN - 0169-5002
VL - 82
SP - 305
EP - 312
JO - Lung Cancer
JF - Lung Cancer
IS - 2
ER -