Clinical research of gene therapy using tissue-specific promoter for the treatment of metastatic prostate cancer.

背景：激素难治性前列腺癌缺乏有效的治疗方法，需要开发新的治疗方法，如基因治疗，可单独或与现有治疗方法联合应用于晚期前列腺癌的治疗。Ad-OC-TK(含有骨钙素启动子驱动的单纯疱疹病毒胸苷激酶基因的重组腺病毒载体)联合万乃洛韦治疗激素非依赖性前列腺癌的I/II期临床试验在日本神户大学医院进行。方法：选择激素难治性前列腺癌局部复发或骨转移患者6例。局部复发肿瘤或骨转移灶直接注射Ad-OC-TK的剂量为2.5×10~9或10×10~(-1)个斑块形成单位(PFU)/d1和d8。患者给予Val1克，每日2次，共21天。结果：最初的患者对该疗法耐受性良好，未发生严重不良事件。尽管进行了瘤内注射，但HSVtk和腺病毒基因都能够在外周血样本中检测到。用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法(TUNEL)检测，每例皮损的活检组织在治疗后均有HSVtk、CAR和OC蛋白的转录表达，并观察到细胞凋亡增加。最初，6例患者中有4例血清PSA水平下降，与万乃洛韦前药物激活HSV-TK一致。核素骨显像定量分析显示，RI仅在注射部位积聚减少。结论：Ad-OC-TK联合Val治疗作为一种组织特异性OC启动子为基础的毒性基因治疗，在最初的日本激素不敏感的前列腺癌患者中显示了局部的抗肿瘤作用，没有任何严重的不良反应。

Background : The absence of effective therapies for hormone refractory prostate cancer establishes the need to develop novel therapeutic modality, such as a gene therapy, that can be applied either separately or in conjunction with current treatment modalities for the treatment of advanced prostate cancer. The phase I/II clinical trial of the Ad-OC-TK (recombinant adenoviral vector containing osteocalcin promoter driven herpes-simplex-virus thymidine kinase gene) plus VAL (Valacyclovior) for the treatment of hormone-refractory prostate cancer was performed at the Kobe University Hospital, Japan.. Method : To date, six patients with localized recurrence or bone metastasis of hormone refractory prostate cancer were enrolled. The doses of a Ad-OC-TK injected directly to localized recurrent tumor or bone metastatic lesion was 2.5 x 10^9 or 10^<10> plaque-forming unit (PFU) / Day 1 and Day 8. Patient was given one gram of VAL twice daily for 21 days. Results : The initial patients tolerated this therapy without serious adverse events. Despite intralesional injections, both the hsvTK and adenoviral genes were able to detect in peripheral blood samples. Biopsies of each lesion demonstrated hsvTK, CAR and OC proteins after treatment demonstrating transcriptional expression in these specimens and increased apoptosis post-treatment observed by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay. Initially, serum PSA levels declined in 4 out of 6 patients coincident with valacyclovir pro-drug activation of hsv-TK. The quantitative analysis of bone scintigraphy showed the decreased RI accumulation only in injected lesion. Conclusions : The Ad-OC-TK plus VAL therapy as a tissue-specific OC promoter-based toxic gene therapy has demonstrated the localized anti-tumor effect without any serious adverse events in the initial Japanese patients with hormone-refractory prostate cancer.