がん温熱遺伝子治療の開発にむけて

DOI Web Site 参考文献31件
  • 大津留 晶
    長崎大学医学部原爆後障害医療研究施設分子医療部門
  • ブライデン ベラ
    長崎大学医学部原爆後障害医療研究施設分子医療部門
  • 三木 文夫
    長崎大学医学部原爆後障害医療研究施設分子医療部門
  • 磯本 一
    長崎大学医学部原爆後障害医療研究施設分子医療部門 長崎大学医学部第2内科学教室
  • 赤司 有史
    長崎大学医学部原爆後障害医療研究施設分子医療部門 長崎大学医学部第2外科学教室
  • 小坂 光男
    長崎大学医学部第2内科学教室 長崎大学熱帯医学研究施設環境生理部門
  • 山下 俊一
    長崎大学医学部原爆後障害医療研究施設分子医療部門

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  • Interdisciplinary Approach by Hyperthermia and Cancer Gene Therapy.

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Hyperthermic therapy has been applied in many advanced malignancies, but tumor regression occurs only in thermo-sensitive cancers. To elucidate ways to overcome thermo-resistance and to improve the therapeutic efficiency of treating thermo-resistant cancers, we devised a novel application of cancer gene therapy in conjunction with hyperthermia. This strategy allows for selective cancer gene therapy under control of the heat-inducible HSP promoter. Heat-inducible activity of HSP promoter was examined in FM3A breast cancer cell line and MKN45 gastric cancer cell line using a luciferase assay reporter gene system. HSP promoter activity increased markedly following heat shock, and this increase depended on temperature and duration of treatment. Based on these results, we designed a suicide gene therapy using the Herpes simplex virus thymidine kinase gene ligated to the heat-inducible HSP promoter (HSP-tk). In in vitro cytotoxic assays HSP-tk transduced cells following heat treatment became 50, 000 times more sensitive than either non-transduced cells or HSP-tk transduced cells without heat treatment to ganciclovir (GCV). Immunohistochemical analysis revealed that Fas-mediated apoptosis was involved in the synergistic killing effect of combination therapy. Next, we examined the efficacy of HSP-tk gene therapy in vitro, cancer cell lines implants in subcutaneous or intraperitoneal models of balb/c nude mice were targeted using the HVJ-anionic-liposome method. Significant inhibition of tumor growth was observed in HSP-tk transduced tumors following hyperthermia as more than half of treated-mice showed complete tumor eradication. Prolonged survival was also observed in HSP-tk transducted mice with hyperthermia. In contrast, non-transduced mice treated with or without hyperthermia showed no prolongation of survival. Recently, another group reported an in vitro study that HSP promoter-mediated gene therapy is an effective treatment for prostate cancer studied. Taken together, these results demonstrate that the combined gene and hyperthermic therapy may be a feasible treatment that can target HSP-expressing carcinomas, even in advanced cases.

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