CPT-11 (SN-38) chemotherapy may be selectively applicable to biliary tract cancer with low hMLH1 expression.
CPT-11 (SN-38) chemotherapy may be selectively applicable to biliary tract cancer with low hMLH1 expression.
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发表时间：
2007-03
影响因子：
2
通讯作者：
Ken Sato;Y. Kitajima;Naohiko Kohya;Y. Koga;Kazuma Ohtaka;K. Miyazaki
中科院分区：
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作者：
Ken Sato;Y. Kitajima;Naohiko Kohya;Y. Koga;Kazuma Ohtaka;K. Miyazaki
胆道癌是一种恶性程度很高的肿瘤，5年生存率很低。然而，已建立的化疗方案尚未建立。以前，我们曾报道过错配修复基因hMLH1在手术切除的胆道癌中经常缺失(57%)，并且hMLH1表达缺失的患者预后比那些有hMLH1表达的患者预后更差。MMR基因被认为与对作用于DNA的各种化疗药物的敏感性有关。据报道，MMR表达的缺失会增加拓扑异构酶抑制剂如依托泊苷(ETP)或喜树碱(CPT)的敏感性。在本研究中，利用短干扰(Si)RNA系统研究了hMLH1缺失是否导致伊立替康(CPT-11)活性形式(SN-38)的敏感性增加。采用定量逆转录聚合酶链式反应(RT-PCR)检测7种肿瘤细胞株hMLH1的表达水平，并与SN-38的药物敏感性(IC50)进行比较。HMLH1的表达与SN-38的IC50值相关，但无统计学意义(R=0.717，p=0.0715)。将siRNA双链RNA(DsRNA)瞬时导入KMG-C(胆囊癌)细胞。与对照dsRNA相比，hMLH1 dsRNA以剂量依赖的方式抑制hMLH1mRNA的表达。SN-38对hMLH1双链RNA转染组细胞生长的抑制作用约为50%。流式细胞仪检测SN-38对细胞周期的影响。HMLH1 dsRNA转染后，与对照组相比，亚G1期细胞比例增加，且呈剂量依赖关系。总之，hMLH1在胆道癌中的低表达可能有助于预测其对CPT-11(SN38)的反应性。
Biliary tract cancer is of highly malignancy with a poor 5-year survival. However, established chemotherapeutic regimens have not yet been established. Previously, we have reported that hMLH1, a mismatch repair (MMR) gene was frequently (57%) found to be lacking in surgically resected biliary tract carcinomas and the patients lacking the expression of hMLH1 revealed a poorer prognosis than those patients who possessed it. The MMR gene has been considered to be associated with sensitivity to various chemotherapeutic agents that act on DNA. A loss of MMR expression has been reported to increase sensitivity to topoisomerase inhibitors such as etoposide (ETP) or camptothecins (CPT). In the present study, whether or not hMLH1 deficiency resulted in a higher sensitivity to irinotecan (CPT-11) active form (SN-38) was investigated using a short interfering (Si)RNA system. A quantitative reverse transcription-polymerase chain reaction (RT-PCR) was conducted to measure the levels of hMLH1 expression in seven cancer cell lines, and this was compared with the drug sensitivity (IC50) to SN-38. The hMLH1 expression was correlated with the IC50 for SN-38, although the relationship was not statistically significant (R = 0.717, p = 0.0715). SiRNA double strand RNA (dsRNA) was transiently transfected into KMG-C (gallbladder cancer) cells. hMLH1 mRNA expression was repressed by hMLH1 dsRNA in a dose-dependent manner in comparison to the control dsRNA. The cell growth of the hMLH1 dsRNA transfected group was decreased by approximately 50% by SN-38 exposure. Flow cytometry was also carried out to examine the effect of the SN-38 treatment on the cell cycle. Following hMLH1 dsRNA transfection, the subG1 fraction was increased in comparison with the control in a dose-dependent manner. In conclusion, a low expression of hMLH1 in biliary tract cancer may aid in predicting its responsiveness to CPT-11 (SN38).