Incorporating the survivin promoter in an infectivity enhanced CRAd-analysis of oncolysis and anti-tumor effects in vitro and in vivo

Zhu, Zeng B.; Makhija, Sonia K.; Lu, Baogen; Wang, Minghui; Rivera, Angel A.; Kim‐Park, SangAe; Ulasov, Ilya V.; Zhou, Fen; Alvarez, Ronald D.; Siegal, Gene P.; Curiel, David T.

doi:10.3892/ijo.27.1.237

Cited by 31 publications

(36 citation statements)

References 42 publications

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“…To date, however, few glioma-relevant promoter elements have been suggested and well characterized for employment in CRAds. We have previously shown that the survivin promoter is upregulated in brain tumors (2,3) and that the human survivin promoter represents a novel transcriptional targeting strategy in malignant glioma (1). Consequently, in the present investigation, we utilized the survivin promoter to drive the expression of an oncolytic adenovirus and analyzed the mechanism of viral induced cell killing in the setting of malignant glioma.…”

Section: Discussionmentioning

confidence: 99%

“…Our group has shown that the survivin promoter appears to be a promising tumor-specific promoter in in vivo gene therapy of human melanoma, breast cancer, cholangiocarcinoma, and malignant glioma (1)(2)(3)(4). We have also shown the selectivity of survivin-modified adenovectors for malignant glial cells rather than normal human astrocytes (5).…”

Section: Introductionmentioning

confidence: 92%

“…All of the recombinant viruses (AdWT, CRAd-S-RGD) have been previously described (3). Briefly, AdWT, and its isogenic control AdRGD virus having RGD motif incorporated into fiber protein, are replication competent vectors (23).…”

Section: Recombinant Virusesmentioning

confidence: 99%

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Oncolytic adenoviral vectors which employ the survivin promoter induce glioma oncolysis via a process of beclin-dependent autophagy

et al. 2009

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Abstract. Survivin has gained attention as a tumor-specific marker which is upregulated in a variety of neoplasms. Although the survivin protein is implicated in anti-apoptotic tumor pathways, little is known about the function of the survivin promoter. In this study, we constructed a conditionally replicative adenoviral vector (CRAd) that utilizes the survivin promoter and examined the mechanism of CRAd induced cell death in malignant glioma. Our results indicate that CRAd vectors which utilize the survivin promoter effectively replicate in glioma cells and exhibit a high oncolytic effect. The survivin-mediated CRAd appeared to induce apoptosis as measured by Annexin/7-AAD. Caspase-3 and BAX mRNAs were upregulated based on microarray data, however, Western blot analysis of infected cells showed no evidence of elevated caspase-3, BAX, or p53 protein expression. Of note, at each time point infected glioma cells showed no evidence of activated BAD or AKT. The inhibition of AKT signaling led us to examine autophagy in infected cells. Electron micrographs of virally infected glioma cells suggested autophagosomal-mediated cell death and selective blocking of beclin with siRNA prevented autophagy. These results indicate that the survivin promoter enhances viral replication and induces autophagy of infected glioma cells via a beclindependent mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

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Oncolytic adenoviral vectors which employ the survivin promoter induce glioma oncolysis via a process of beclin-dependent autophagy

et al. 2009

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“…The survivin promoter appears to be a promising tumorspecific promoter in the context of human melanoma, breast cancer, and glioma. 27,[36][37][38] Most recently, survivin has been found to be overexpressed in up to 79% of astrocytic tumors. [39][40][41] The expression of this gene correlates with grade and is present in 90% of glioblastomas.…”

Section: Discussionmentioning

confidence: 99%

Comparative evaluation of survivin, midkine, and CXCR4 promoters for transcriptional targeting of glioma gene therapy

Ulasov¹,

Rivera²,

Sonabend³

et al. 2007

Cancer Biology & Therapy

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Objective: Transcriptional targeting is a key strategy to enhance therapeutic efficacy of gene therapy applications. In the context of oncolytic virotherapy, transcriptional promoter elements are used from genes that are over expressed in a variety of malignant cancers. In the present study, we examined the feasibility of transcriptional targeting to glioma cells by comparing the activity of survivin, midkine, and CXCR4 tumor-specific promoters.Methods: To evaluate the expression level of several glioma related genes, we performed quantitative RT-PCR analyses on samples obtained from cell lines and patients. To determine specific level of gene expression mediated by selective promoter elements, we measured luciferase expression in glioma samples transduced with replication deficient adenoviral vectors. Finally, we incorporated the optimal promoters into a conditionally replicative adenoviral vector, CRAd-5/3, and examined the cytopathic effect in vitro.Results: The survivin promoter demonstrated the highest level of mRNA expression in primary tumor samples and cell lines. Transcriptional targeting was confirmed by infection of glioma cells with an adenovirus expression vector containing a survivin-driven luciferase reporter gene. Of the tested promoters, minimal level of survivin activity was detected in normal human liver and brain. A novel vector, CRAd-survivin5/3, with E1a under the control of the survivin promoter, exhibited enhanced cytopathic effect in vitro.Conclusions: Our data demonstrate that the survivin promoter element is very active in glioma samples and has low activity in normal human brain and liver. A novel oncolytic virus, CRAd-survivin-5/3, was effective against a panel of glioma cell lines in vitro. Our results suggest that employing the survivin promoter element in the context of CRAd-5/3 may present a new opportunity for the development of glioma specific oncolytic vectors.

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“…In this assay, the presence of the E4 gene was determined using real-time PCR from DNA samples extracted from medium after 1, 3, and 9 days post-infection [26,27]. Viral replication was also determined in cells infected with an untargeted replicative Ad-wt-dE3 as a positive control and in cells infected with a non-replicative Ad-CXCR4-GL3 as a negative control.…”

Section: Eif4e Selective Replication Of Dual-level Targeted Cradsmentioning

confidence: 99%

Cancer-specific targeting of a conditionally replicative adenovirus using mRNA translational control

Stoff-Khalili

Rivera

Nedeljkovic-Kurepa

et al. 2007

Breast Cancer Res Treat

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Background-In view of the limited success of available treatment modalities for a wide array of cancer, alternative and complementary therapeutic strategies need to be developed. Virotherapy employing conditionally replicative adenoviruses (CRAds) represents a promising targeted intervention relevant to a wide array of neoplastic diseases. Critical to the realization of an acceptable therapeutic index using virotherapy in clinical trials is the achievement of oncolytic replication in tumor cells, while avoiding non-specific replication in normal tissues. In this report, we exploited cancer-specific control of mRNA translation initiation in order to achieve enhanced replicative specificity of CRAd virotherapy agents. Heretofore, the achievement of replicative specificity of CRAd agents has been accomplished either by viral genome deletions or incorporation of tumor selective promoters. In contrast, control of mRNA translation has not been exploited for the design of tumor specific replicating viruses to date. We show herein, the utility of a novel approach that combines both transcriptional and translational regulation strategies for the key goal of replicative specificity.

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Incorporating the survivin promoter in an infectivity enhanced CRAd-analysis of oncolysis and anti-tumor effects in vitro and in vivo

Cited by 31 publications

References 42 publications

Oncolytic adenoviral vectors which employ the survivin promoter induce glioma oncolysis via a process of beclin-dependent autophagy

Oncolytic adenoviral vectors which employ the survivin promoter induce glioma oncolysis via a process of beclin-dependent autophagy

Comparative evaluation of survivin, midkine, and CXCR4 promoters for transcriptional targeting of glioma gene therapy

Cancer-specific targeting of a conditionally replicative adenovirus using mRNA translational control

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