[Effect of gefitinib on radiosensitivity of gastric cancer cell lines].
OBJECTIVE
Epidermal growth factor receptor (EGFR) is expressed in most human epithelial cancers and is involved in the development of cancer cell resistance to irradiation. We used gefitinib, a selective EGFR tyrosine kinase inhibitor (EGFR-TKI), to investigate its effects and mechanisms in enhancing the radiosensitivity of human gastric cancer cell lines in vitro.


METHODS
The expression of EGFR protein in 7 human gastric cell lines (MKN45, SGC7901, SNU-1, N87, AGS, SNU-16, and KATO-III) was determined by Western blot, in which 2 cell lines with high expression of EGFR were selected for additional test. The inhibitory effect of gefitinib on cell proliferation was measured by MTT assay. Cell survival was determined by clonogenic assay, and then the radiosensitivity parameters were calculated. The effects of gefitinib in combination with radiation on cell apoptosis and cell cycle distribution were analyzed by flow cytometry.


RESULTS
Of the 7 gastric cancer cell lines, the expression of EGFR in MKN45 and SGC7901 cells were the highest. The 50% inhibition concentrations (IC(50)) of gefitinib were 0.4 mmol/L for MKN45 cells and 0.8 mmol/L for SGC7901 cells. Cell survival was significantly decreased with the elevation of gefitinib concentration or radiation dose (P<0.05). When treated with 0.1x and 0.2 x IC(50) of gefitinib, the radiosensitization enhancement ratios (SER) of MKN45 cells were 1.102 and 1.154, and those of SGC7901 cells were 1.092 and 1.176, respectively. Either gefitinib or radiation induced cell apoptosis, reduced the percentage of cells at S phase and increased the percentage of cells at G(2)/M phase (P<0.01).


CONCLUSIONS
Gefitinib followed by radiation could increase the radiosensitivity of MKN45 and SGC7901 cells with high expression of EGFR and inhibit cell proliferation, induce apoptosis, and alter cell phase distribution. Gefitinib could be a radiation sensitizer for gastric tumors with high expression of EGFR.
Cao
Wei-Guo
WG
Department of Oncology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025, PR China.
Ma
Tao
T
Li
Jian-Fang
JF
Li
Hao
H
Ji
Yu-Bao
YB
Chen
Xue-Hua
XH
Liu
Bing-Ya
BY
Jin
Ye-Ning
YN
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077156:Gefitinib; D006801:Humans; D010315:Particle Accelerators; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000473:pathology*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D066246:ErbB Receptors; D000077156:Gefitinib