Oxaliplatin in treatment of the cisplatin-resistant MKN45 cell line of gastric cancer.
OBJECTIVE
The clinical efficiency of cisplatin (CDDP) against gastric cancer is often limited by the development of resistance. A third-generation platinum-containing agent, oxaliplatin (L-OHP), has been introduced for treating gastric cancer. Here, we studied oxaliplatin in vitro to reveal the mechanism of acquiring drug resistance and whether a cisplatin-resistant gastric cancer cell line has susceptibility to oxaliplatin.


METHODS
A cisplatin-resistant gastric cancer cell line (MKN45/CDDP/ R1) was established by continuous exposure of MKN45 cells to cisplatin. The amount of excision repair cross-complementation group 1 (ERCC1) and glutathione-S-transferase (GST)-pi mRNA was measured by real-time polymerase chain reaction (PCR). To examine the chemosensitivity to CDDP and L-OHP in MKN45 and MKN45/CDDP/R1 cells, a collagen gel droplet-embedded culture drug sensitivity test (CD-DST) was performed. The intracellular concentration of CDDP and L-OHP were also measured to see if the drugs would be taken up by these cell lines.


RESULTS
The MKN45/CDDP/R1 cell line was resistant to CDDP. The ERCC1 and GST-pi mRNA was significantly increased in MKN45/CDDP/R1 cells, indicating that the cells acquired resistance to CDDP. Intracellular CDDP was not detected in MKN45/CDDP/R1 cells up to 48 h after incubation, indicating that uptake and efflux processes of CDDP were altered in these cells. MKN45/CDDP/R1 cells were still susceptible to L-OHP. The intracellular concentration of CDDP but not L-OHP was significantly reduced in MKN45/CDDP/R1 cells.


CONCLUSIONS
We established a CDDP-resistant cell line using MKN45 cells, in which ERCC1 and GST-pi were increased. This cell line showed susceptibility to the new generation platinum agent L-OHP, suggesting this anticancer agent could be used in second-line treatment of patients with CDDP-resistant gastric neoplasms.
Tozawa
Katsuyuki
K
Division of Lower Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Oshima
Tadayuki
T
Kobayashi
Takehiko
T
Yamamoto
Noriyasu
N
Hayashi
Chizuko
C
Matsumoto
Takayuki
T
Miwa
Hiroto
H