肝癌组织特异性MGMT干扰腺病毒载体促进奥沙利铂杀伤肝癌细胞的作用及机制研究

FOLFOX chemotherapy with oxaliplatin provides a new choice for the treatment of advanced hepatocellular carcinoma(HCC), our previous experimental results and literature suggests that DNA damage and repair mediated by MGMT in human HCC cells may be an important cause of HCC cell spontaneous resistance effect against oxaliplatin, but normal liver cells need to maintain a certain degree of MGMT activity to avoid malignant transformation or being killed by chemotherapy. On this basis, this research was designed to constructs a HCC-specific MGMT interference adenovirus vector, specificly inhibit MGMT expression in AFP-positive cells, so as to achieve a HCC-s[ecific inhibition against MGMT activity. And then evaluate the effect of MGMT interference vector on oxaliplatin-induced cytotoxocity effect om HCC cells in vitro and in vivo, initially uncover the molecular mechanism of MGMT interference on promote the oxaliplatin killing HCC cells from DNA crosslinking, injury, cell cycle arrest and apoptosis aspects via DNA damage repair pathway, to provide a new ideas to promote the chemotherapy on liver cancer, to offer a reference for further attempts on improving the effect of chemotherapy of hepatocellular carcinoma.

含奥沙利铂的folfox化疗方案为晚期肝癌的治疗提供了新的选择，申请人前期实验结果及既往文献提示，肝癌细胞中MGMT介导的DNA损伤修复可能是引起肝癌细胞自发性耐药抵抗奥沙利铂作用的重要原因，但正常肝细胞中又需要保持一定程度的MGMT活性以避免恶变或被化疗药物杀伤。在此基础上，本课题拟构建肝癌组织特异性MGMT干扰腺病毒载体，特异性抑制AFP高表达细胞中MGMT的表达水平，从而达到特异性抑制肝癌细胞中MGMT活性，并在体外及裸鼠体内两个层面探讨特异性MGMT干扰载体对奥沙利铂抗肝癌作用的效果，并从DNA交联、损伤、细胞周期阻滞及凋亡等方面初步揭示MGMT干扰载体促进奥沙利铂杀伤肝癌细胞的分子机制，为从DNA损伤修复途径促进化疗药物抗肝癌作用提供新的思路，为进一步改善肝癌的化疗效果提供借鉴。

含奥沙利铂的folfox化疗方案为晚期肝癌的治疗提供了新的选择，申请人前期实验结果及既往文献提示，肝癌细胞中MGMT介导的DNA损伤修复可能是引起肝癌细胞自发性耐药抵抗奥沙利铂作用的重要原因，但正常肝细胞中又需要保持一定程度的MGMT活性以避免恶变或被化疗药物杀伤。在此基础上，本课题通过构建肝癌组织特异性MGMT干扰腺病毒载体，特异性抑制AFP高表达细胞中MGMT的表达水平，从而达到特异性抑制肝癌细胞中MGMT活性，在体外及裸鼠体内两个层面探讨特异性MGMT干扰载体对奥沙利铂抗肝癌作用的效果，为从DNA损伤修复途径促进化疗药物抗肝癌作用提供新的思路，为进一步改善肝癌的化疗效果提供借鉴。