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

Abstract

OBJECTIVES:

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: Minoru Kobayashi, Takashi Okada, Takashi Murakami, Keiya Ozawa, Eiji Kobayashi, Tatsuo Morita
• Journal: Urology (Urology) Vol. 70 Issue 6 Pg. 1230-6 (Dec 2007) ISSN: 1527-9995 [Electronic] United States
• PMID: 18158067 (Publication Type: Journal Article)

Chemical References

• Antibiotics, Antineoplastic
• Bridged-Ring Compounds
• Clmp protein, rat
• Coxsackie and Adenovirus Receptor-Like Membrane Protein
• Depsipeptides
• Histone Deacetylase Inhibitors
• Lactones
• Receptors, Virus
• uprolide F
• romidepsin

Topics

• Adenoviridae (genetics, growth & development)
• Animals
• Antibiotics, Antineoplastic (therapeutic use)
• Bridged-Ring Compounds
• Carcinoma, Renal Cell (therapy)
• Coxsackie and Adenovirus Receptor-Like Membrane Protein
• Depsipeptides (therapeutic use)
• Gene Transfer Techniques
• Genes, Transgenic, Suicide
• Genetic Therapy
• Genetic Vectors
• Histone Deacetylase Inhibitors
• Kidney Neoplasms (therapy)
• Lactones
• Male
• Rats
• Rats, Inbred ACI
• Receptors, Virus (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Xenograft Model Antitumor Assays