Tumor-specific activation of hTERT-derived promoters by tumor suppressive E1A-mutants involves recruitment of p300/CBP/HAT and suppression of HDAC-1 and defines a combined tumor targeting and suppression system

Kirch, Hans-Christoph; Ruschen, S; Brockmann, Dieter; Esche, Helmut; Horikawa, Izumi; Barrett, J. Carl; Opalka, Bertram; Hengge, Ulrich R.

doi:10.1038/sj.onc.1205965

Cited by 24 publications

(16 citation statements)

References 37 publications

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“…protein can activate the promoter activity of the hTERT gene (41,42). Therefore, to determine whether OBP-301 infection activates hTERT mRNA expression, we examined the expression level of hTERT mRNA in ALT-type U2OS cells after infection with OBP-301 at MOIs of 10 and 100 PFUs/cell (Fig.…”

Section: Resultsmentioning

confidence: 99%

Preclinical Evaluation of Telomerase-Specific Oncolytic Virotherapy for Human Bone and Soft Tissue Sarcomas

Sasaki

Tazawa

Hasei

et al. 2011

Clinical Cancer Research

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Purpose: Tumor-specific replication-selective oncolytic virotherapy is a promising antitumor therapy for induction of cell death in tumor cells but not of normal cells. We previously developed an oncolytic adenovirus, OBP-301, that kills human epithelial malignant cells in a telomerase-dependent manner. Recent evidence suggests that nonepithelial malignant cells, which have low telomerase activity, maintain telomere length through alternative lengthening of telomeres (ALT). However, it remains unclear whether OBP-301 is cytopathic for nonepithelial malignant cells. Here, we evaluated the antitumor effect of OBP-301 on human bone and soft tissue sarcoma cells.Experimental Design: The cytopathic activity of OBP-301, coxsackie and adenovirus receptor (CAR) expression, and telomerase activity were examined in 10 bone (OST, U2OS, HOS, HuO9, MNNG/HOS, SaOS-2, NOS-2, NOS-10, NDCS-1, and OUMS-27) and in 4 soft tissue (CCS, NMS-2, SYO-1, and NMFH-1) sarcoma cell lines. OBP-301 antitumor effects were assessed using orthotopic tumor xenograft models. The fiber-modified OBP-301 (termed OBP-405) was used to confirm an antitumor effect on OBP-301-resistant sarcomas.Results: OBP-301 was cytopathic for 12 sarcoma cell lines but not for the non-CAR-expressing OUMS-27 and NMFH-1 cells. Sensitivity to OBP-301 was dependent on CAR expression and not on telomerase activity. ALT-type sarcomas were also sensitive to OBP-301 because of upregulation of human telomerase reverse transcriptase (hTERT) mRNA following virus infection. Intratumoral injection of OBP-301 significantly suppressed the growth of OST and SYO-1 tumors. Furthermore, fiber-modified OBP-405 showed antitumor effects on OBP-301-resistant OUMS-27 and NMFH-1 cells.Conclusions: A telomerase-specific oncolytic adenovirus is a promising antitumor reagent for the treatment of bone and soft tissue sarcomas.

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Section: Resultsmentioning

confidence: 99%

Preclinical Evaluation of Telomerase-Specific Oncolytic Virotherapy for Human Bone and Soft Tissue Sarcomas

Sasaki

Tazawa

Hasei

et al. 2011

Clinical Cancer Research

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“…Firstly, hTERT promoter was used to control the expression of E4 gene in Ad.EHT2. It is known that hTERT promoter can be potentially stimulated by adenoviral E1A protein, either directly or as a consequence of the activation of the cell cycle (Kirch et al, 2002). AdEHT2 virus could express E1A protein in IMR-90 cells, so the selectivity of hTERT promoter in IMR-90 cells may be lost owing to the E1A expression.…”

Section: Discussionmentioning

confidence: 99%

A novel oncolytic adenovirus targeting to telomerase activity in tumor cells with potent

et al. 2004

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Telomerase is a therapeutic target for cancer. Human telomerase reverse transcriptase (hTERT), the catalytic subunit of the telomerase, is transcriptionaly upregulated exclusively in about 90% of cancer cells. Previous studies have demonstrated that hTERT promoter can control the expression of exogenous genes to the telomerase-positive cancer cells, thus hTERT promoter is an excellent candidate for generating cancer-specific oncolytic adenovirus. In this study, we devised a novel oncolytic adenovirus (Ad.TERT) by replacing the normal E1A regulatory elements with hTERT promoter. Ad.TERT displays cancer-specific E1A expression, virus replication and cytolysis in in vitro experiments. In animal experiments, intratumoral administration of Ad.TERT demonstrates potent antitumoral efficacy at least in two xenograft models (Bcap37 and BEL7404). Ad.TERT was targeted by the telomerase activity in cancer cells and has potent antitumoral efficacy in vivo, and since telomerase activity is a wide-ranged tumor marker, Ad.TERT could be a powerful therapeutic agent for a variety of cancers.

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“…Telomerase induction is achieved either through transcriptional promoter activation (e.g. HPV E6 oncoprotein [27], adenoviral E1 [28] …”

Section: Telomerase Regulation In Cancermentioning

confidence: 99%

Telomerase-Dependent Gene Therapy

Wirth

Kühnel²,

Kubicka³

2005

CMM

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Adenovirus-mediated gene therapy approaches have evolved as promising means for cancer treatment during the last decade. Utilizing a broad spectrum of tumor-specific promoters, numerous oncotropic vectors have been created with exceptional properties regarding tumor-restricted specificity. The discovery of telomerase, its high prevalence in tumor tissues and the discovery of its transcriptional regulation via the hTERT promoter have extended the applicability of adenoviral gene therapy vectors to approximately 90% of all tumors. First generation adenoviral vectors expressing transgenes under the control of the hTERT promoter confirmed the therapeutic potential but were restricted to initially transduced cancer cells. Recently, telomerase-dependent conditionally replicative adenoviral vectors (CRADs) have been developed that combine the specificity of hTERT promoter based expression systems with the lytic efficacy of replicative viruses. To evaluate the potential for clinical applications, various efforts have been made to establish combinative strategies including systemic chemotherapy, radiotherapy and antiangiogenesis. This review highlights the rapid advances of telomerase-based gene therapy and gives insight into future prospects and future development of oncotropic vectors.

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Tumor-specific activation of hTERT-derived promoters by tumor suppressive E1A-mutants involves recruitment of p300/CBP/HAT and suppression of HDAC-1 and defines a combined tumor targeting and suppression system

Cited by 24 publications

References 37 publications

Preclinical Evaluation of Telomerase-Specific Oncolytic Virotherapy for Human Bone and Soft Tissue Sarcomas

Preclinical Evaluation of Telomerase-Specific Oncolytic Virotherapy for Human Bone and Soft Tissue Sarcomas

A novel oncolytic adenovirus targeting to telomerase activity in tumor cells with potent

Telomerase-Dependent Gene Therapy

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