Heat-directed suicide gene therapy mediated by heat shock protein promoter for gastric cancer.
Heat-directed suicide gene therapy mediated by heat shock protein promoter for gastric cancer.
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DOI：
10.3892/or.15.3.629
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发表时间：
2006-03
期刊：
影响因子：
4.2
通讯作者：
H. Isomoto;A. Ohtsuru;V. Braiden;M. Iwamatsu;Fumio Miki;Y. Kawashita;Y. Mizuta;Y. Kaneda;S. Kohno;S. Yamashita
中科院分区：
文献类型：
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作者：
H. Isomoto;A. Ohtsuru;V. Braiden;M. Iwamatsu;Fumio Miki;Y. Kawashita;Y. Mizuta;Y. Kaneda;S. Kohno;S. Yamashita
转移性胃癌，特别是腹膜转移癌，患者的预后仍然很差，尽管加强干预。基因治疗和热疗可能是治疗这种晚期疾病的有前途的策略。本研究旨在探讨单纯疱疹病毒胸苷激酶（HSV-tk）自杀基因治疗联合热疗治疗进展期胃癌的可能途径。建立了以热休克蛋白（hsp）70 B基因启动子为导向的HSV-tk（HSP-tk）/更昔洛韦（GCV）系统。采用双荧光素酶法检测热调控下胃癌细胞株和裸鼠移植瘤中热休克蛋白启动子的活性。使用由日本血凝病毒（HVJ）脂质体递送的HSP-tk/GCV，在加热或不加热的情况下进行体外细胞毒性测定。用HVJ脂质体携带的HSP-tk对皮下异种移植肿瘤和腹膜癌转移的小鼠进行热疗和基因治疗。通过荧光素酶测定的评估证明了体外和体内高度可诱导的和肿瘤特异性的启动子活性。细胞毒性实验表明，转染HSP-tk的细胞对加热的GCV更敏感。当用非热诱导型巨细胞病毒（CMV）启动子介导的HSV-tk/GCV和加热处理时，也观察到协同效应，表明旁观者杀伤。HVJ-脂质体介导的HSP-tk/GCV联合热疗能显著抑制皮下肿瘤的生长，延长腹腔转移癌小鼠的生存期。我们的结论是自杀基因治疗与热疗的结合可以为晚期胃癌提供一种有前途的治疗方式。
The prognosis of patients with metastatic gastric cancer, particularly peritoneal carcinomatosis, remains poor despite intensive interventions. Gene therapy and hyperthermia can be promising strategies for such advanced disease. The study was conducted to explore the possible effective therapeutic approach of suicide gene therapy with herpes simplex virus thymidine kinase (HSV-tk) in combination with hyperthermia for advanced gastric cancer. The heat shock protein (hsp) 70B gene promoter-oriented HSV-tk (HSP-tk)/ganciclovir (GCV) system directed by heat shock was developed. Hsp promoter activity under the control of heating was assessed by dual luciferase assay in gastric cancer cell lines and implanted tumors of nude mice. In vitro cytotoxic assay was performed using the HSP-tk/GCV delivered by the hemagglutinating virus of Japan (HVJ) liposome, with or without heating. Mice with subcutaneously xenografted tumors and peritoneal carcinomatosis were treated with hyperthermia and gene therapy using the HVJ-liposome-carrying HSP-tk. Assessment by luciferase assay demonstrated highly inducible and tumor-specific promoter activity in vitro and in vivo. Cytotoxic assays showed that cells transfected with HSP-tk became more sensitive to GCV with heating. A synergistic effect was also observed when treated with a non-heat-inducible cytomegalovirus (CMV) promoter-mediated HSV-tk/GCV and heating, indicating bystander killing. The HVJ-liposome-carrying HSP-tk/GCV combined with hyperthermia significantly inhibited the growth of subcutaneous tumors and prolonged survival of mice with peritoneal carcinomatosis. We conclude that the combination of suicide gene therapy with hyperthermia can provide a promising treatment modality for advanced gastric cancer.