[Cytotoxic effect of epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in combination with oxaliplatin on lung cancer cell line A549].
OBJECTIVE
ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has clinical antitumor activity, but its efficacy is low. This study was to assess the effects of ZD1839 in combination with oxaliplatin on lung adenocarcinoma cell line A549, and to provide pre-clinical evidence for optimizing the schedule of oxaliplatin combined with ZD1839.


METHODS
Chou and Talalay method was used to analyze the combination effects of sequencing ZD1839 and oxaliplatin on A549 cells. Cell cycle distribution and cell apoptosis were analyzed by flow cytometry. The effects of oxaliplatin combined with ZD1839 on the proliferation of A549 cells in nude mice were also evaluated.


RESULTS
Sequential oxaliplatin followed by ZD1839 produced synergistic effect, with a combination index (CI) of 0.51+/-0.01. In contrast, ZD1839 followed by oxaliplatin exhibited antagonist effect, with a CI of 1.56+/-0.03. Compared with other sequences, oxaliplatin followed by ZD1839 induced more cells being arrested in G(2/M) phase (37.9%, P<0.05); the apoptosis rate was 22.3%. The inhibition rate of tumor growth in nude mice was 58.9% when treated with oxaliplatin followed by ZD1839, 52.4% when treated with oxaliplatin and ZD1839 for 24 h and followed by ZD1839 for additional 48 h, and 30.6% when treated with ZD1839 followed by oxaliplatin.


CONCLUSIONS
Sequential oxaliplatin followed by ZD1839 has the maximal inhibitory effect on the proliferation of A549 cells.
Zhao
Chuan-Hua
CH
Department of Gastrointestinal Oncology, The Affiliated Hospital, Academy of Military Medical Sciences, Beijing, 100071, PR China.
Yuan
Shou-Jun
SJ
Wang
Yan
Y
Ge
Fei-Jiao
FJ
Luo
Wei-Dong
WD
Xu
Jian-Ming
JM
D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000077150:Oxaliplatin; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077150:Oxaliplatin; D066246:ErbB Receptors; D000077156:Gefitinib