Tissue-targeted in vivo gene transfer coupled with histone deacetylase inhibitor depsipeptide (FK228) enhances adenoviral infection in rat renal cancer allograft model systems.
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.
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
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