A Histone Deacetylase Inhibitor Enhances Adenoviral Infection of Renal Cancer Cells

Purpose: Coxsackie and adenovirus receptor is a high affinity receptor for adenovirus type 5. To our knowledge the expression profile of coxsackie and adenovirus receptor in renal cancer has not been described. We evaluated the expression of coxsackie and adenovirus receptor in human renal cancer specimens and determined whether the histone deacetylase inhibitor FK-228 (Astelas Pharmaceutical, Osaka, Japan) increases the efficiency of adenoviral infections in renal carcinoma cells in vivo and in vitro. Materials and Methods: We used randomly selected renal cancer specimens. Specimens were analyzed for coxsackie and adenovirus receptor expression using reverse transcriptase-polymerase chain reaction and immunohistochemistry. In vitro experiments on cytotoxicity were performed to determine a nontoxic dose of FK-228 for renal cancer cells. The level of coxsackie and adenovirus receptor expression was determined by fluorescence activated cell scanning and/or reverse transcriptase-polymerase chain reaction in FK-228 treated renal cancer cells. The effect in vivo on adenoviral gene expression was investigated in athymic mice. Results: In several human renal cancer specimens a loss of or decreased coxsackie and adenovirus receptor expression was detected by reverse transcriptase-polymerase chain reaction based analysis and immunohistochemistry. The nontoxic dose of FK-228 for renal carcinoma cells was 0.5 ng/ml. Treatment of cancer cells with 0.5 ng/ml FK-228 increased levels of coxsackie and adenovirus receptor RNA and acetylated histone H3. This increase was associated with an approximately 10-fold increase in adenoviral infection, as evidenced by increased transgene expression from a β-galactosidase containing adenoviral vector. Intravenous administration of FK-228 enhanced coxsackie and adenovirus receptor expression in athymic mice. The combination of β-galactosidase adenovirus and FK-228 was significantly more effective than adenovirus only in A498 cells 3 weeks after treatment in vivo. The combination of p21 adenovirus and FK-228 resulted in significant tumor inhibition in vitro and in vivo. Conclusions: In human renal cancer specimens a loss of or decrease in coxsackie and adenovirus receptor expression may be an early event in renal cancer progression. Pretreatment with FK-228 may increase tumor cell sensitivity to adenoviral gene therapy vectors.