title: Tissue-targeted in vivo gene transfer coupled with histone deacetylase inhibitor depsipeptide (FK228) enhances adenoviral infection in rat renal cancer allograft model systems.
abstract: OBJECTIVE
  Although the adenoviral vector represents an efficient delivery system, hepatotropic accumulation often has detrimental effects on adenoviral vector-mediated cancer therapy. To overcome this disadvantage, we performed in vivo local gene transfer, in combination with the histone deacetylase inhibitor, depsipeptide (FK228), in a rat renal cancer model.
  
  
  METHODS
  Renal cancer cells induced by ferric nitrilotriacetate in ACI rats were used in this study. Adenoviral vectors containing luciferase cDNA were introduced into the tumor-burdened kidney by way of a catheter placed in the renal artery. Subcutaneous tumors were treated by herpes simplex virus thymidine kinase cDNA followed by intraperitoneal ganciclovir. The levels of Coxsackie-adenovirus receptor in various tissue were determined by quantitative reverse transcriptase-polymerase chain reaction. Depsipeptide (1 mg/kg) was intravenously administered 24 hours before adenoviral vector transduction.
  
  
  RESULTS
  The catheter-based adenoviral vector delivery enabled strong gene transduction of the tumor-burdened kidney. Moreover, depsipeptide treatment before adenoviral vector injection significantly improved transgene expression at tumor sites. Quantitative reverse transcriptase-polymerase chain reaction analysis showed that depsipeptide increased the expression levels of the Coxsackie-adenovirus receptor in the renal tumor (13-fold), but not in other normal tissues. Furthermore, the use of herpes simplex virus thymidine kinase cDNA-expressing adenoviral vector followed by ganciclovir markedly inhibited the established tumor growth in combination with depsipeptide compared with herpes simplex virus thymidine kinase cDNA alone.
  
  
  CONCLUSIONS
  The tissue-targeted in vivo gene transfer coupled with depsipeptide significantly enhanced adenoviral infection at tumor sites. Sensitization of tumor cells with depsipeptide can improve the efficacy of adenoviral vector-mediated suicide gene therapy. Thus, application of depsipeptide could be one of the beneficial adjunct for adenoviral vector-mediated cancer gene therapy.
authors.affiliation: Department of Urology, Jichi Medical University, Tochigi, Japan. minoruk@jichi.ac.jp
authors.forename: Minoru
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Okada
authors.forename: Takashi
authors.initials: T
authors.lastname: Murakami
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
authors.forename: Eiji
authors.initials: E
authors.lastname: Kobayashi
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Morita
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000254:growth & development; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001952:Bridged-Ring Compounds; D002292:Carcinoma, Renal Cell / Q000628:therapy*; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D047630:Depsipeptides / Q000627:therapeutic use*; D018014:Gene Transfer Techniques; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy; D005822:Genetic Vectors; D056572:Histone Deacetylase Inhibitors; D007680:Kidney Neoplasms / Q000628:therapy*; D007783:Lactones; D008297:Male; D051381:Rats; D011912:Rats, Inbred ACI; D011991:Receptors, Virus / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D001952:Bridged-Ring Compounds; C568773:Clmp protein, rat; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D007783:Lactones; D011991:Receptors, Virus; C416984:uprolide F; C087123:romidepsin