Midkine promoter-based conditionally replicative adenovirus for malignant glioma therapy

Kohno, Shohei; Nakagawa, Kou; Hamada, Katsuyuki; Harada, Hironobu; Yamasaki, Kenshi; Hashimoto, Koji; Tagawa, Masatoshi; Nagato, Shigeyuki; Furukawa, Koji; Ohnishi, Takanori

doi:10.3892/or.12.1.73

Cited by 24 publications

(27 citation statements)

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“…32 In the case of glioma, midkine promoter activity was shown to be two times higher in midkine-positive cells than in midkine-negative primary normal brain cells. 35 For this reason, a midkine promoter-based CRAd (Ad-MK) was developed. 27 This vector showed strong oncolytic activity in midkine-positive glioma cells but did not exhibit cytotoxicity in midkine-negative primary normal brain cells.…”

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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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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“…[19][20][21] Briefly, pShuttle2-PL/hMKpro þ E1A-E1B, 22 which possesses the E1A and E1B gene under the control of the midkine promoter, 23 was digested with I-CeuI/PI-SceI and ligated with the I-CeuI/PI-SceIdigested pAdHM3. 20 The resulting plasmid, pAdHM3-hMKpro, was transfected into 293 cells using the Superfect transfection reagent after digestion with PacI in order to generate a conventional CRAd based on Ad5 (CRAd-F5).…”

Section: Preparation Of Crads and Carrier Cellsmentioning

confidence: 99%

Efficient antitumor effects of carrier cells loaded with a fiber-substituted conditionally replicating adenovirus on CAR-negative tumor cells

et al. 2011

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“…We examined tyrosinase mRNA expression in glioma and normal tissues by quantitative RT-PCR, using the expression of the midkine (MK) gene as an internal positive control because of its characteristic over-expression in gliomas (2,24,25). As shown in Fig.…”

Section: Analysis Of Tyrosinase Mrna In Gliomamentioning

confidence: 99%

“…To achieve tumor specificity, one of the approaches consists of exploring the distinct transcriptional profile found in tumor cells. This principle can be applied to target oncolytic adenoviral vectors, so called CRAds (1)(2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

An oncolytic adenoviral vector carrying the tyrosinase promoter for glioma gene therapy

et al. 2007

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Abstract. Targeting gene expression to cancer cells remains a challenge for the development of gene and viral therapy for gliomas. Recent studies have highlighted transcriptional targeting as one of the possible solutions to overcome this limitation. In this context, melanoma associated antigens (MAAs) are usually over-expressed in brain tumors in comparison to normal brain tissue. For this reason, we investigated the use of the tyrosinase promoter as a transcriptional element to target oncolytic therapy for gliomas. Tyrosinase mRNA expression was evaluated by qRT-PCR in normal human brain tissue as well as in human glioma specimens. We found that this gene was significantly overexpressed in glioma cell lines and in primary glioma samples. Tyrosinase expression correlated with the grade of the tumor (p-value range: 0.05-0.001). Furthermore, transfection of several cell cultures with human and mouse tyrosinase promoters driving a luciferase reporter gene confirmed the activity of this promoter in mouse and human cells. To evaluate whether tyrosinase-activated conditionally replicative adenoviruses (CRAds) could induce toxicity in glioma cells, two vectors (Ad h/m and Ad24TYR) were tested in a mouse glioma model. C57BL/6 mice underwent intracranial injection of tumor cell line GL261. Survival was used to evaluate efficacy of the tested vectors. Mice receiving 1x10 9 MOI of Ad h/m and Ad24TYR following intracranial tumor implants had a median survival of 46±3 days (p<0.05); in contrast, those treated with medium had a median survival of 31±2 days.These results suggest that injection of tyrosinase CRAds leads to prolongation of survival in mice with experimental brain tumors. The tyrosinase promoter stands as a proof of principle of the potential use of MAA over-expression patterns for targeting novel anti-glioma therapies.

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Midkine promoter-based conditionally replicative adenovirus for malignant glioma therapy

Cited by 24 publications

References 0 publications

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

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

Efficient antitumor effects of carrier cells loaded with a fiber-substituted conditionally replicating adenovirus on CAR-negative tumor cells

An oncolytic adenoviral vector carrying the tyrosinase promoter for glioma gene therapy

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