Preclinical biodistribution and safety study of reduced expression in immortalized cells/Dickkopf-3-encoding adenoviral vector for prostate cancer gene therapy

Abstract

The biodistribution and safety of adenoviral vectors encoding the human REIC/Dkk-3 tumor suppressor gene (Ad-REIC) were examined in this preclinical study for in situ prostate cancer gene therapy. First, the in vitro apoptotic effects of Ad-REIC in normal and cancer cells derived from the prostate and liver were examined. Significant apoptotic effects were observed at 100 MOI (multiplicity of infection) in prostate cancer cells (LNCaP, PC3) and hepatoma cells (HEP3B and HEPG2); however, no effects were seen in normal cells. To analyze the safety of intraprostatic Ad-REIC administration, the biodistribution and histology after Ad-REIC injection were evaluated in various organs of normal male C57BL6 mice. In a supporting study, vector dissemination following intravenous injection of Ad-REIC into tail veins was determined. To evaluate whether Ad-REIC was present in the collected tissue specimens, human REIC gene detection was performed using DNA-PCR. Intraprostatic treatment administered at lower doses showed vector biodistribution into the colon, urinary bladder and prostate. At higher doses, vector dissemination was observed in tissues more distant from the prostate, including the lung, thymus, heart, liver and adrenal gland. After intravenous injection of Ad-REIC, dissemination was observed in the liver and spleen. These results indicate that the biodistribution of Ad-REIC is determined by the dose and route of administration. Although acute inflammatory effects were observed in the prostate after intraprostatic administration at higher doses, no abnormal histological findings were noted in the other tissues, including those of intravenously treated mice. Regarding the safety of Ad-REIC administration, no deaths and no signs of toxicity or unusual behavior were observed in the mice in any treatment group. Based on these preclinical experiments, adenovirus-mediated in situ REIC/Dkk-3 gene therapy is considered to be safe for use as a treatment for human prostate cancer.

Anti-Cancer Effects of REIC/Dkk-3-encoding Adenoviral Vector for the Treatment of Non-small Cell Lung Cancer

“…As for administration strategy, local administration might be preferable rather than systemic administration to minimize the adverse effect in clinical situations. We previously confirmed in mouse model that Ad-REIC could be widely distributed in the bodies after intratumoral local administration, and local administration was effective not only directly but also indirectly through the immune system effect [16], [23]. In addition, intrapleural local administration could be another administration strategy for the patients with malignant pleural effusions.…”

Dihydrotestosterone inhibits arylsulfatase B and Dickkopf Wnt signaling pathway inhibitor (DKK)‐3 leading to enhanced Wnt signaling in prostate epithelium in response to stromal Wnt3A

“…Attenuation of TGF‐β signaling in prostate cancer following CRISPR‐mediated reactivation of DKK3 expression has been reported . Gene therapy with DKK3 has been proposed for treatment of prostate cancer (NCT01931046) …”

Adenovirus-mediated REIC/Dkk-3 gene therapy: Development of an autologous cancer vaccination therapy (Review)

“…Adenovirus-mediated gene delivery continues to be the preferred treatment for cancer as the vectors indicate the high transduction efficacy of the therapeutic gene and the safety of the procedure when used for direct local injection (5–7). A number of previous clinical trials have demonstrated the utility and safety of the intratumoral injection of adenoviral vectors in cancer lesions (7).…”