Gefitinib Enhances Cytotoxicities of Antimicrotubule Agents in Non–Small-Cell Lung Cancer Cells Exhibiting No Sensitizing Epidermal Growth Factor Receptor.

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Gefitinib Enhances Cytotoxicities of Antimicrotubule Agents in Non–Small-Cell Lung Cancer Cells Exhibiting No Sensitizing Epidermal Growth Factor Receptor Mutation Chun-Ming Tsai, MD, Chao-Hua Chiu, MD, Kao-Ting Chang, PhD, Jen-Ting Chen, MD, Chun-Liang Lai, MD, Yuh-Min Chen, MD, PhD, Shih-Yin Hsiao, BSc Journal of Thoracic Oncology Volume 7, Issue 8, Pages 1218-1227 (August 2012) DOI: 10.1097/JTO.0b013e318258cf17 Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 The expression levels of four multiple-drug resistance-associated transcripts (MDR1, BCRP, MRP1, and MRP2) in the 17 tested cell lines were determined by real-time quantitative reverse transcription polymerase chain reaction. In a particular cell line, the gene level was normalized to glyceraldehyde-3-phosphate dehydrogenase (ΔCt). The relative gene expression level was calculated using the equation 2−ΔΔCt as the value relative to that of the calibrator sample (NCI-H23). Mean values and 95% confidence intervals (error bars) generated from three independent assays are shown. Journal of Thoracic Oncology 2012 7, 1218-1227DOI: (10.1097/JTO.0b013e318258cf17) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 A, Mean combination index (mCI) distribution of gefitinib/gemcitabine, gefitinib/paclitaxel, gefitinib/docetaxel, and gefitinib/vinorelbine of the 15 cell lines derived from tumors of previously untreated patients (T). The group results are shown and expressed as mCI values (see Materials and Methods) with 95% confidence intervals (error bars). Of these 15 cell lines, three had (M) and 12 had no (W) sensitizing epidermal growth factor receptor mutations. B, The subgroup results of various gefitinib-drug combinations by sensitizing-epidermal growth factor receptor mutation status are shown and expressed as mCIs with 95% confidence intervals (error bars). C, Statistical analyses of the group difference between regimens were done by the Wilcoxon signed rank test. The group mCIs for gefitinib/gemcitabine, gefitinib/paclitaxel, gefitinib/docetaxel, and gefitinib/vinorelbine combinations are designated mCIGGe, mCIGP, mCIGD, and mCIGN, respectively. N.S., no statistically significant difference. (Shaded area in A and B: additivism based on a null interval of 0.95–1.05.) mCI, mean combination index. Journal of Thoracic Oncology 2012 7, 1218-1227DOI: (10.1097/JTO.0b013e318258cf17) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 A, The combination effects of gefitinib plus gemcitabine, paclitaxel, docetaxel, or vinorelbine in NCI-H23 and its Pgp-overexpressing subclones H23-A0.1 and H23-A0.3. The mean combination index values and 95% confidence intervals (error bars) generated from the three independent assays performed in quadruplicate are plotted. Signed tests were applied to evaluate whether antagonism (Ant) or synergism (S) was evident for a particular cell line and drug combination. Otherwise, the interaction was additivism (Ad). The differences in drug interactions between cell lines were analyzed using the Wilcoxon signed rank test. Numbers in brackets are the number of data points. (Shaded area: additivity based on a null interval of 0.95–1.05.) B, Inhibition of the rhodamine 6G fluorescence-effluxing capacity of adenosine-5′ triphosphate-binding cassette transporters by gefitinib at 0.3 to 10 μM. Rhodamine 6G was used as the fluorescence probe to imitate anticancer agents. Reserpine, a P-glycoprotein inhibitor, was used as a positive control. C, The isobolograms of gefitinib/vinorelbine in H1155 cells (a), gefitinib/paclitaxel in H226 cells (b), and gefitinib/vinorelbine in HCC827 cells (c). Data points above the dash diagonal line representing the additive effect in the isobole suggest antagonism, and those below the diagonal suggest synergism. (Shaded area: the area where the concentration of gefitinib ⩽ 5% of IC50) Journal of Thoracic Oncology 2012 7, 1218-1227DOI: (10.1097/JTO.0b013e318258cf17) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 The effects of gefitinib on the dose-versus-log-response curves of paclitaxel, docetaxel, or vinorelbine in six NSCLC cell lines. A, H838 cells, expressing almost undetectable levels of Pgp, had an additive gefitinib/paclitaxel interaction. B, H23-A0.1 cells, with induced P-glycoprotein (Pgp)-overexpression, had a synergistic gefitinib/docetaxel interaction. C, H125 cells, exhibiting nearly undetectable Pgp levels, showed a synergistic gefitinib/vinorelbine interaction. D, H1299 and E, H1155 cells, both expressing de novo Pgp, showed a synergistic gefitinib/paclitaxel and gefitinib/vinorelbine interaction, respectively. F, H226 cells, with nearly undetectable Pgp levels, showed a synergistic gefitinib/docetaxel interaction (see Results). Mean survival fraction and 95% confidence intervals (error bars) generated from three independent assays performed in quadruplicate are shown. The mCIs for gefitinib/paclitaxel, gefitinib/docetaxel, and gefitinib/vinorelbine combinations are designated mCIGP, mCIGD, and mCIGN, respectively. mCI, mean combination index. Journal of Thoracic Oncology 2012 7, 1218-1227DOI: (10.1097/JTO.0b013e318258cf17) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions