A novel hTERT promoter–driven E1A therapeutic for ovarian cancer

Xie, Xiaoming; Hsu, Jennifer L.; Choi, Min Gew; Xia, Weiya; Yamaguchi, Hirohito; Chen, Chun‐Te; Trinh, Bon Q.; Lü, Zhen; Ueno, Naoto T.; Wolf, Judith K.; Bast, Robert C.; Hung, Mien‐Chie

doi:10.1158/1535-7163.mct-09-0056

Cited by 33 publications

(30 citation statements)

References 40 publications

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“…The tumor-specific hTERT promoter has been successfully used in the gene therapy of ovarian cancer (21,22). Nevertheless, the activity of the hTERT promoter in ovarian tumor cells is often too low for effective targeted gene therapy (5). The TSTA system, including the transcriptional activator GAL4-VP16 and G5E4T regulatory element (a small promoter that is responsive to GAL4), has markedly enhanced the activity of the corresponding TSP (23,24).…”

Section: Discussionmentioning

confidence: 99%

“…Although numerous promoters have been used in targeted gene therapy for ovarian cancer, including secretory leukocyte protease inhibitor, ovarian-specific promoter and human epithelial tissue-specific transcription factor promoter, these promoters are neither ovarian cancer-specific nor epithelium-specific, and may even be active in normal cells (3). By contrast, the human telomerase reverse transcriptase (hTERT) promoter is only activated in ovarian cancer cells with high telomerase activity, and therefore is highly suitable for the gene therapy of ovarian cancer (4,5). However, the activity of tumor-specific promoters is often too weak to mediate the desired gene therapy (6).…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic effect of targeted Fas-expressing adenoviruses method combining γδ T cells in a mouse model of human ovarian carcinoma

Zeng

Lin

et al. 2017

Oncol Lett

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Abstract. The present study aimed to investigate the therapeutic effect and safety of targeted use of Fas-expressing adenoviruses combined with γδ T cell-mediated killing to treat human ovarian cancer xenografts in BALB/c mice. Shuttle plasmids containing control elements of human telomerase reverse transcriptase promoter and two-step transcriptional amplification system were constructed and packaged into adenovirus-5 vectors to generate expression of an exogenous Fas gene. A mouse xenograft model of human ovarian carcinoma was constructed. A total of 35 BALB/c mice were randomly divided into five groups, which were injected with PBS, γδ T cells, Fas-expressing adenoviruses, taxol, or Fas-expressing adenovirus and γδ T cells. The weight and volume of tumors in mice in each group was monitored. Tissue sections of the various tissues of mice in the Fas-expressing adenovirus and γδ T cells group was compared with those in the PBS group to evaluate the safety of Fas-expressing adenovirus and γδ T cells in the treatment of human ovarian cancer xenograft tumors. The results of the present study indicated that mice in all treatment groups were alive at the end of the treatment course. Tumor weight and volume was the highest in the PBS group, followed successively by the adenovirus group, the γδ T cell group, the adenovirus and γδ T cell group, and the taxol group. The weight and volume inhibition rate in adenovirus and γδ T cell group were significantly higher compared with in the PBS group (P<0.05). Pathological observation of tissue samples revealed that none of vital organs in the adenovirus and γδ T cell group developed any evident morphological changes during treatment, when compared with healthy controls. In conclusion, the combined therapy with Fas-expressing adenoviruses and γδ T cells is efficient and safe for the treatment of mouse human ovarian carcinoma xenografts.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Therapeutic effect of targeted Fas-expressing adenoviruses method combining γδ T cells in a mouse model of human ovarian carcinoma

Zeng

Lin

et al. 2017

Oncol Lett

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“…The human telomerase reverse transcriptase (T) is highly expressed in a majority of cancer types but not in normal cells, which allows it to be used as a tumor biomarker (15,17,18). Previously, we identified and validated the specificity of the T promoter in ovarian cancer and showed that its activity was enhanced by the VISA amplification system (15).…”

Section: Discussionmentioning

confidence: 99%

“…Plasmids pGL3-T-Luc, pGL3-Survivin-Luc, pGL3-Clandin-4-Luc, pGL3-FASN-Luc, pGL3-b-cateinin-Luc, and pGL3-CMV-Luc containing the T, survivin, claudin-4, FASN, b-catenin, and CMV promoter, respectively, to drive the expression of the firefly luciferase gene were previously described (14,15,19,21,26). The VISA amplification system was incorporated into the pGL3-T-Luc plasmid to create pGL3-T-VISA-Luc.…”

Section: Preparation Of Plasmids and Liposomementioning

confidence: 99%

“…The development of current viral vectors for targeted treatment is restricted by a number of issues such as immunogenicity, toxicity (10,11), and potential recombination or complementation (12). Luckily, nonviral promoterbased targeted therapy has gained widespread attention for its cancer specificity, optimal antitumor activities, and less toxicity to surrounding normal cells (13)(14)(15)(16). Thus, a promoter that is highly active and specific for breast tumor would be ideal for designing such targeted therapy.…”

Section: Introductionmentioning

confidence: 99%

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Targeted Expression of BikDD Eliminates Breast Cancer with Virtually No Toxicity in Noninvasive Imaging Models

Xie

Xiao

et al. 2012

Molecular Cancer Therapeutics

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Breast cancer is a major public health problem all over the world, and the current treatment strategies are not potent enough for some patients, especially those with triple-negative breast cancer. Therefore, novel and more effective treatments are critically needed. Of the current methods, targeted therapy, which not only retains cancer-specific expression but also limits toxicity, is a new strategy for treating cancers. In this study, we found that the human telomerase reverse transcriptase (hTERT; T) promoter also possesses high target specificity in breast cancer. Moreover, we developed a versatile T-based breast cancer-specific promoter VISA (VP16-Gal4-WPRE integrated systemic amplifier) composite (T-VISA) to target transgene expression in breast tumors, which has stronger activity comparable or higher than that of the cytomegalovirus promoter in cancer cells. Thereafter, targeted expression of BikDD (a mutant form of proapoptotic gene Bik) through the T-VISA platform in breast cancer initiated robust antitumor effects and prolonged survival in multiple xenograft and syngeneic orthotopic mouse models of breast tumors with virtually no toxicity in intact mice. Thus, these findings show that our T-VISA-BikDD nanoparticles effectively and safely eradicate breast cancer in vitro and in vivo and are worthy of development in clinical trials treating breast cancer. Mol Cancer Ther; 11(9); 1915-24. Ó2012 AACR.

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Cancer Gene Therapy by Tissue‐specific and Cancer‐targeting Promoters

Hsu

Huo

et al. 2014

Cancer Gene Therapy by Viral and Non‐viral Vectors

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A novel hTERT promoter–driven E1A therapeutic for ovarian cancer

Cited by 33 publications

References 40 publications

Therapeutic effect of targeted Fas-expressing adenoviruses method combining γδ T cells in a mouse model of human ovarian carcinoma

Therapeutic effect of targeted Fas-expressing adenoviruses method combining γδ T cells in a mouse model of human ovarian carcinoma

Targeted Expression of BikDD Eliminates Breast Cancer with Virtually No Toxicity in Noninvasive Imaging Models

Cancer Gene Therapy by Tissue‐specific and Cancer‐targeting Promoters

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