Oxaliplatin in treatment of the cisplatin-resistant MKN45 cell line of gastric cancer.
Oxaliplatin in treatment of the cisplatin-resistant MKN45 cell line of gastric cancer.
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发表时间：
2008-07
影响因子：
2
通讯作者：
Katsuyuki Tozawa;T. Oshima;Takehiko Kobayashi;N. Yamamoto;Chizuko Hayashi;T. Matsumoto;H. Miwa
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作者：
Katsuyuki Tozawa;T. Oshima;Takehiko Kobayashi;N. Yamamoto;Chizuko Hayashi;T. Matsumoto;H. Miwa
背景与目的顺铂（cisplatin，CDDP）治疗胃癌的临床疗效往往受到耐药的限制。第三代含铂剂奥沙利铂（L-OHP）已被引入用于治疗胃癌。本研究旨在探讨奥沙利铂的体外耐药机制及顺铂耐药胃癌细胞株对奥沙利铂的敏感性。材料与方法采用顺铂持续作用于MKN 45细胞，建立胃癌顺铂耐药细胞系MKN 45/CDDP/ R1。采用实时荧光定量聚合酶链反应（PCR）检测切除修复交叉互补组1（ERCC 1）和谷胱甘肽-S-转移酶（GST）-π mRNA的表达。为了检测MKN 45和MKN 45/CDDP/R1细胞对CDDP和L-OHP的化疗敏感性，进行胶原凝胶液滴包埋培养药物敏感性试验（CD-DST）。还测量了CDDP和L-OHP的细胞内浓度，以观察药物是否会被这些细胞系摄取。结果MKN 45/CDDP/R1细胞对顺铂耐药。MKN 45/CDDP/R1细胞ERCC 1和GST-pi mRNA表达明显增加，表明细胞对CDDP产生了耐药性。在孵育后48 h内，在MKN 45/CDDP/R1细胞中未检测到胞内CDDP，表明这些细胞中CDDP的摄取和外排过程发生了改变。MKN 45/CDDP/R1细胞对L-OHP仍敏感。在MKN 45/CDDP/R1细胞中，CDDP而不是L-OHP的细胞内浓度显著降低。结论利用MKN 45细胞建立了CDDP耐药细胞系，其ERCC 1和GST-pi表达增加。该细胞系对新一代铂类药物L-OHP敏感，提示该抗癌药物可用于CDDP耐药胃癌患者的二线治疗。
BACKGROUND AND AIM 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. MATERIALS AND 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. CONCLUSION 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.