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

使用组织特异性启动子的基因治疗治疗转移性前列腺癌的临床研究。

基本信息

批准号：
14207063
负责人：
KAMIDONO Sadao
金额：
$ 28.12万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2005
项目状态：
已结题

项目摘要

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.

背景资料：缺乏对激素难治性前列腺癌的有效治疗确立了开发新的治疗模式（例如基因治疗）的需要，所述治疗模式可以单独地或与当前治疗模式结合应用以治疗晚期前列腺癌。在日本科比大学医院进行了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）联合瓦尔（伐昔洛韦）治疗难治性前列腺癌的I/II期临床试验。方法：迄今为止，6例激素难治性前列腺癌局部复发或骨转移患者入选。直接注射至局部复发性肿瘤或骨转移病灶的Ad-OC-TK剂量为2.5 x 10^9或10^9空<10>斑形成单位（PFU）/第1天和第8天。患者接受1 g瓦尔，每日两次，持续21天。结果：最初的患者耐受这种治疗，没有严重的不良事件。尽管病灶内注射，hsvTK和腺病毒基因都能够检测到外周血样本。每个病灶的活检证实了治疗后的hsvTK、CAR和OC蛋白，证实了这些标本中的转录表达，并通过末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）测定观察到治疗后细胞凋亡增加。最初，6例患者中有4例血清PSA水平下降，与伐昔洛韦前体药物激活hsv-TK一致。骨密度定量分析显示仅在注射病灶处RI降低。结论：Ad-OC-TK加瓦尔疗法作为一种基于组织特异性OC启动子的毒性基因疗法，已在最初的日本难治性前列腺癌患者中证明了局部抗肿瘤作用，且无任何严重不良事件。