In vitro sequence-dependent synergism between paclitaxel and gefitinib in human lung cancer cell lines

• Published in: Cancer chemotherapy and pharmacology Vol. 67; no. 3; pp. 637 - 646
• Main Authors: Cheng, Hua, An, She-Juan, Zhang, Xu-Chao, Dong, Song, Zhang, Yi-Fang, Chen, Zhi-Hong, Chen, Hua-Jun, Guo, Ai-Lin, Lin, Qiu-xiong, Wu, Yi-Long
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.03.2011; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biological and medical sciences; Cancer Research; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Cell Cycle - drug effects; Cell Line, Tumor; Drug Administration Schedule; Drug Synergism; Epidermal growth factor receptor tyrosine kinase; Humans; Lung cancer; lung neoplasms; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Medical sciences; Medicine; Medicine & Public Health; Oncology; Original Article; Paclitaxel - administration & dosage; Pharmacology. Drug treatments; Pharmacology/Toxicology; Phosphorylation - drug effects; Pneumology; Quinazolines - administration & dosage; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Signal Transduction - drug effects; Tumors of the respiratory system and mediastinum; Lung cancer; Epidermal growth factor receptor tyrosine kinase; Antineoplastic agent; Quinazoline derivatives; Bronchopulmonary; Epidermal growth factor receptor; Taxane derivatives; Established cell line; Paclitaxel; Bronchus disease; Drug interaction; Gefitinib; Antimitotic; Protein-tyrosine kinase; Tumor cell; Human; Lung disease; Enzyme; Tyrosine kinase inhibitor; Respiratory disease; Transferases; Enzyme inhibitor; Malignant tumor; In vitro; Growth factor receptor; Cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-010-1347-4

Purpose In clinical trials, the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) administered concomitantly with first-line cytotoxicity chemotherapy failed to confer a survival benefit to patients with non-small-cell lung cancer (NSCLC). The aim of this study was to test whether paclitaxel followed by gefitinib is superior to other treatment schedules of NSCLC cell lines and to clarify the underlying mechanisms. Methods Human lung cancer cell lines with wild-type and mutant-type EGFR genes were used as in vitro models to define the differential effects of various schedules of paclitaxel with gefitinib treatment on cell growth, signaling pathway, and cell cycle distribution. Results Sequence-dependent antiproliferative effects differed between EGFR-TKI-resistant and EGFR-TKI-sensitive lung cancer cell lines. Exposure to paclitaxel resulted in an increased pEGFR level. This increase in phosphorylation was inhibited by subsequent exposure to gefitinib, whereas during the reverse sequence, the inhibition effect was reduced. After paclitaxel exposure, a higher level of pEGFR was observed in mitotic than in interphase cells. The sequence of paclitaxel followed by gefitinib resulted in greater anti-VEGF activity than did the reverse sequence. We confirmed that gefitinib arrested cells in G1, and paclitaxel arrested them in S phase. The sequence of paclitaxel followed by gefitinib arrested cells in G1, whereas the reverse sequence arrested cells in S and G2 phases. Conclusions These findings suggest that the sequence of paclitaxel followed by gefitinib may be superior to other sequences in treating NSCLC cell lines. Our results also provide molecular evidence to support clinical treatment strategies for patients with lung cancer.