Heat-directed suicide gene therapy mediated by heat shock protein promoter for gastric cancer.
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.
Isomoto
Hajime
H
Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan. hajimei2002@yahoo.co.jp
Ohtsuru
Akira
A
Braiden
Vera
V
Iwamatsu
Miyoko
M
Miki
Fumio
F
Kawashita
Yujo
Y
Mizuta
Yohei
Y
Kaneda
Yasufumi
Y
Kohno
Shigeru
S
Yamashita
Shunichi
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D006979:Hyperthermia, Induced; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D016019:Survival Analysis; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D012333:RNA, Messenger; D013937:Thymidine Kinase; D015774:Ganciclovir