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

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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.