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

Morito Sugimoto, Masami Watanabe, Haruki Kaku, Shun A I Li, Hirofumi Noguchi, Hideo Ueki, Masakiyo Sakaguchi, Nam H O Huh, Yasutomo Nasu, Hiromi Kumon

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1645-1652
Number of pages8
JournalOncology Reports
Volume28
Issue number5
DOIs
Publication statusPublished - Nov 2012

Fingerprint

Neoplasm Genes
Genetic Therapy
Prostate
Prostatic Neoplasms
Safety
Intravenous Injections
Liver
Adrenal Glands
Tumor Suppressor Genes
Adenoviridae
Thymus Gland
Tail
Hepatocellular Carcinoma
Veins
Histology
Colon
Urinary Bladder
Therapeutics
Spleen
Polymerase Chain Reaction

Keywords

  • Adenovirus vector
  • Biodistribution
  • Gene therapy
  • Prostate cancer
  • Reduced expression in immortalized cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Preclinical biodistribution and safety study of reduced expression in immortalized cells/Dickkopf-3-encoding adenoviral vector for prostate cancer gene therapy. / Sugimoto, Morito; Watanabe, Masami; Kaku, Haruki; Li, Shun A I; Noguchi, Hirofumi; Ueki, Hideo; Sakaguchi, Masakiyo; Huh, Nam H O; Nasu, Yasutomo; Kumon, Hiromi.

In: Oncology Reports, Vol. 28, No. 5, 11.2012, p. 1645-1652.

Research output: Contribution to journalArticle

Sugimoto, Morito ; Watanabe, Masami ; Kaku, Haruki ; Li, Shun A I ; Noguchi, Hirofumi ; Ueki, Hideo ; Sakaguchi, Masakiyo ; Huh, Nam H O ; Nasu, Yasutomo ; Kumon, Hiromi. / Preclinical biodistribution and safety study of reduced expression in immortalized cells/Dickkopf-3-encoding adenoviral vector for prostate cancer gene therapy. In: Oncology Reports. 2012 ; Vol. 28, No. 5. pp. 1645-1652.
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