In vitro sequence-dependent synergism between paclitaxel and gefitinib in human lung cancer cell lines.
OBJECTIVE
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.
Cheng
Hua
H
Guangdong Lung Cancer Institute, Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, People's Republic of China.
An
She-Juan
SJ
Zhang
Xu-Chao
XC
Dong
Song
S
Zhang
Yi-Fang
YF
Chen
Zhi-Hong
ZH
Chen
Hua-Jun
HJ
Guo
Ai-Lin
AL
Lin
Qiu-Xiong
QX
Wu
Yi-Long
YL
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects
D011799:Quinazolines; D066246:ErbB Receptors; D017239:Paclitaxel; D000077156:Gefitinib