Publications (4)21.36 Total impact
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Article: Androgen receptor attenuation of Ad5 replication: implications for the development of conditionally replication competent adenoviruses.
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ABSTRACT: Conditionally replication competent adenoviruses (CRAds) represent one of the most intensely studied gene therapy strategies for a variety of malignancies, including prostate cancer. These viruses can be generated by placing a tissue or cancer-specific promoter upstream of one or more of the viral genes required for replication (e.g., E1A, E1B). We report here that E1A inhibits androgen receptor (AR) target gene induction and, correspondingly, activated AR inhibits adenoviral replication. This mutual inhibition appears to be an indirect effect, possibly through competition for shared transcriptional co-activators. The net effect is that the oncolytic effect of prostate-specific CRAds is attenuated by these interactions. Fusion of the E1A to AR ameliorates this inhibition, while enhancing specificity. These findings have significant implications in the development of prostate-specific CRAd therapies.Molecular Therapy 09/2007; 15(8):1495-503. · 6.87 Impact Factor -
Article: Valproic acid inhibits invasiveness in bladder cancer but not in prostate cancer cells.
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ABSTRACT: Histone deacetylase inhibitors (HDACIs) represent a promising new class of antineoplastic agents that affect proliferation, differentiation, and apoptosis in both solid and hematologic malignancies. In addition, HDACIs can alter the expression of at least one cellular adhesion molecule, the coxsackie and adenovirus receptor, in bladder cancer. Because HDACIs can increase expression of a known cellular adhesion molecule, we hypothesized that migration and/or invasion may also be affected. We evaluated this hypothesis using valproic acid (VPA), a commonly prescribed anticonvulsant recently shown to have potent HDACI activity, in the bladder cancer cell lines T24 TCC-SUP, HT1376, and RT4. Analyses of cell migration and invasion were both qualitative (fluorescent microscopy) and quantitative (static and dynamic migration/invasion assays). Our results show that acute VPA treatment (72 h) causes a dose-dependent decrease in invasion for all bladder cancer cell lines, except RT4, a noninvasive papilloma. Migration, in contrast, was not affected by VPA treatment. The inhibitory effect of VPA may be cancer type-specific, because there was no difference in invasion between treated and untreated prostate cancer cell lines LNCaP, PC3, and DU145. Furthermore, when administered chronically (34 days), VPA significantly inhibits growth of T24t tumor xenografts. Our data suggest that VPA exerts some of its antineoplastic effects by inhibiting invasion as well as tumor growth, and thus it may represent a novel adjuvant strategy for patients at high risk of recurrence and/or progression of muscle invasive bladder cancer.Journal of Pharmacology and Experimental Therapeutics 12/2006; 319(2):533-42. · 3.83 Impact Factor -
Article: Histone deacetylase inhibitors upregulate expression of the coxsackie adenovirus receptor (CAR) preferentially in bladder cancer cells.
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ABSTRACT: Studies on bladder cancer cell lines have shown that low adenoviral (Ad) infectivity is associated with low-level coxsackie adenovirus receptor (CAR) expression. Recently, we and others demonstrated a tumor stage- and grade-dependent downregulation of CAR expression in a large series of clinical bladder cancer specimens. Here, we demonstrate adenoviral gene transfer can be markedly enhanced in bladder cancer cells by upregulation of CAR through the use of certain differentiating agents, including the histone deacetylase inhibitors (HDACI) trichostatin A and sodium phenylbutyrate. CAR upregulation to supraphysiologic levels was demonstrated by quantitative rt-PCR, Western blotting, flow cytometry and adenoviral gene transfer. Normal urothelial cells and CAR-positive papilloma cells (RT4) failed to demonstrate upregulation under the same conditions. Upregulation was cell cycle dependent, associated with increased adenoviral gene transfer and persisted for at least 7 days after a single treatment. Such upregulation, however, appears to be tumor cell specific, as other CAR-negative cell lines failed to demonstrate enhanced adenoviral gene transfer with the same treatments. These results provide a rational basis for combining HDACI therapy with gene therapy as a method of augmenting activity in bladder cancer, but this strategy may not be universally applicable to other cell types.Cancer Gene Therapy 08/2004; 11(7):477-86. · 2.80 Impact Factor -
Article: Prostate-specific expression of the diphtheria toxin A chain (DT-A): studies of inducibility and specificity of expression of prostate-specific antigen promoter-driven DT-A adenoviral-mediated gene transfer.
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ABSTRACT: Diphtheria toxin (DT) is a potent inhibitor of protein synthesis. As little asa single molecule of DT can result in cell-cycle independent cell death. This profound potency has led to difficulties in the development of DT as a suicide gene in cancer gene therapy, because toxicity appears to be related primarily to the fidelity of basal gene expression and the yield of viral titer. We evaluated the feasibility of prostate-specific DT gene therapy by cloning the catalytic domain (A chain) of DT under the control of the prostate-specific antigen (PSA) promoter, the PSA promoter and enhancer, or the cytomegalovirus promoter. The data on expression of DT from the plasmid constructs demonstrate that the basal level of DT gene expression determines the toxicity. To better test the potential therapeutic efficacy of DT suicide gene therapy, we first developed a DT-resistant adenoviral packaging line (293DTR). This allowed us to manufacture a relatively high titer adenoviral vector encoding the DT-A gene under the control of the PSA promoter and enhancer (Ad5PSE-DT-A) as well as an attenuated DT-A virus (Ad5PSE-tox176). In vitro studies showed that our viral constructs preferentially kill PSA-positive prostate cancer cells in the presence of exogenous androgen (R1881). In vivo studies showed that the nu/nu mice with PSA-positive cancer cell LNCaP xenograft treated with wild-type DT-A virus had a rapid regression of tumors and survived over a year without tumor progression, whereas the attenuated DT-A virus restricted tumor growth for only 1 month. The same constructs had no significant effect on the non-PSA-secreting cell line DU-145. These encouraging results suggest that DT-A viral gene transfer may ultimately have a therapeutic role in the treatment of advanced human prostate cancer.Cancer Research 06/2002; 62(9):2576-82. · 7.86 Impact Factor
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2007
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Johns Hopkins University
Baltimore, MD, USA
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2002–2006
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Johns Hopkins Medicine
Baltimore, MD, USA
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