Potent anti-tumor activity of telomerase-dependent and HSV-TK armed oncolytic adenovirus for non-small cell lung cancer in vitro and in vivo

Zhang, Jufeng; Wei, Fang; Wang, Huiping; Li, Huiming; Qiu, Wei; Ren, Peng-Kang; Chen, Xiafang; Huang, Qian

doi:10.1186/1756-9966-29-52

Cited by 35 publications

(28 citation statements)

References 12 publications

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“…It should also be noted that the viral dose (1 Â 10 8 PFU per injection) in this study was much smaller than that used in many previous studies (approximately 1 Â 10 9 PFU), suggesting that more viral doses in future preclinical and clinical studies may result in enhanced efficacy. 26,27 Thus, both the in vitro and in vivo therapeutic potential of Surv.m-CRA-OCp and Surv.m-CRA-CMVp for osteosarcoma in the absence of VD 3 was comparable, suggesting that low E1BD55K expression, that is, extremely weak activity of the altered E1B promoter, is sufficient to exert actual anticancer therapeutic effects.…”

Section: Vd 3 -Dependent Enhancement Of the Osteocalcin Promoter Actimentioning

confidence: 95%

Assessment of an altered E1B promoter on the specificity and potency of triple-regulated conditionally replicating adenoviruses: implications for the generation of ideal m-CRAs

et al. 2011

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Although previous studies modified two components of conditionally replicating adenoviruses (CRAs), which selectively replicate in and kill cancer cells, the most accurate ways to achieve increased cancer specificity (that is, safety) without reducing the anticancer (that is, therapeutic) effects are unknown. Here, we generated two types of survivin-responsive m-CRAs (Surv.mCRAs), Surv.m-CRA-CMVp and Surv.m-CRA-OCp, which use two and three different mechanisms to target cancer, that is, early region 1A (E1A) regulated by the survivin promoter and mutated E1BD55K regulated by the ubiquitously active cytomegalovirus promoter and cancer/tissue-specific osteocalcin promoter, respectively, and carefully examined their safety and anticancer effects. Endogenous osteocalcin mRNA was expressed and further enhanced by vitamin D 3 in all osteosarcoma and prostate cancer cell lines and human osteoblasts, but not in human fibroblasts. The osteocalcin promoter activity was weak even with vitamin D 3 treatment in these osteocalcin-expressing cancers, leading to low E1BD55K expression after Surv.m-CRA-OCp infection. Nevertheless, Surv.m-CRA-OCp had significantly increased cancer specificity without reduced anticancer effects in both in vitro and in vivo experiments. The unexpected but favorable fact that strong activity of an altered E1B promoter is unnecessary indicates that the majority of cancer/tissue-specific promoters may be used to generate ideal m-CRAs and will advance the development of m-CRA-based cancer therapies.

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Section: Vd 3 -Dependent Enhancement Of the Osteocalcin Promoter Actimentioning

confidence: 95%

Assessment of an altered E1B promoter on the specificity and potency of triple-regulated conditionally replicating adenoviruses: implications for the generation of ideal m-CRAs

et al. 2011

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“…31,32 Control mice with HCC were treated with saline. Tumor growth was monitored by calculating the tumor volume from caliper measurements.…”

Section: In Vivo Therapeutic Efficacy Studiesmentioning

confidence: 99%

Assessment of α-Fetoprotein Targeted HSV1-tkExpression in Hepatocellular Carcinoma withIn VivoImaging

Park

Kim

Lee

et al. 2015

Cancer Biotherapy and Radiopharmaceuticals

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Tumor-specific enhancer/promoter is applicable for targeting gene expression in tumors and helpful for tumortargeting imaging and therapy. We aimed to acquire a-fetoprotein (AFP)-producing hepatocellular carcinoma (HCC) specific images using adenovirus containing HSV1-tk gene controlled by AFP enhancer/promoter and evaluate in vivo ganciclovir (GCV)-medicated therapeutic effects on AFP-targeted HSV1-tk expression with 18 F-FDG positron emission tomography (PET). Recombinant adenovirus expressing HSV1-tk under AFP enhancer/promoter was produced (AdAFP-TK) and the expression levels were evaluated by I-IVDU uptake. GCV-mediated HSV1-tk cytotoxicity was determined by MTT assay. After the mixture of AdAFP-fLuc and AdAFP-TK was administrated, bioluminescent images (BLIs) and 18 F-FHBG PET images were obtained in tumor-bearing mice. In vivo therapeutic effects of AdAFP-TK and GCV in the HuH-7 xenograft model were monitored by 18 F-FDG PET. When infected with AdAFP-TK, cell viability in HuH-7 was reduced, but those in HT-29 and SK-Hep-1 were not significantly decreased at any GCV concentration less than 100 lM. AFP-targeted fLuc and HSV1-tk expression were clearly visualized by BLI and 18 F-FHBG PET images in AFP-producing HCC, respectively. In vivo GCV-mediated tumor growth inhibition by AFP-targeted HSV1-tk expression was monitored by 18 F-FDG PET. Recombinant AdAFP-TK could be applied for AFPtargeted HCC gene therapy and imaging in AFP-producing HCC.

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“…This study enrolled sixteen patients with a variety of advanced solid tumors, and determined that a single intratumoral injection of Telomelysin was well tolerated at all doses and generated anti-tumor activity [132]. Based on these results, Phase II trials of Telomelysin are expected, and second-generation viruses that combine telomerase targeted viral replication and suicide gene expression are being developed [133–135]. The use of telomerase-specific viral therapy in combination with irradiation and chemotherapy such as paclitaxel, cisplatin and gemcitabine is also being examined [136–139].…”

Section: Telomerase-directed Viral Therapymentioning

confidence: 99%

Is telomerase a viable target in cancer?

Buseman

Wright

Shay

2012

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

125

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The ideal cancer treatment would specifically target cancer cells yet have minimal or no adverse effects on normal somatic cells. Telomerase, the ribonucleoprotein reverse transcriptase that maintains the ends of human chromosome, is an attractive cancer therapeutic target for exactly this reason [1]. Telomerase is expressed in more than 85% of cancer cells, making it a nearly universal cancer marker, while the majority of normal somatic cells are telomerase negative. Telomerase activity confers limitless replicative potential to cancer cells, a hallmark of cancer which must be attained for the continued growth that characterizes almost all advanced neoplasms [2]. In this review we will summarize the role of telomeres and telomerase in cancer cells, and how properties of telomerase are being exploited to create targeted cancer therapies including telomerase inhibitors, telomerase-targeted immunotherapies and telomerase-driven virotherapies. A frank and balanced assessment of the current state of telomerase inhibitors with caveats and potential limitations will be included.

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Potent anti-tumor activity of telomerase-dependent and HSV-TK armed oncolytic adenovirus for non-small cell lung cancer in vitro and in vivo

Cited by 35 publications

References 12 publications

Assessment of an altered E1B promoter on the specificity and potency of triple-regulated conditionally replicating adenoviruses: implications for the generation of ideal m-CRAs

Assessment of an altered E1B promoter on the specificity and potency of triple-regulated conditionally replicating adenoviruses: implications for the generation of ideal m-CRAs

Assessment of α-Fetoprotein Targeted HSV1-tkExpression in Hepatocellular Carcinoma withIn VivoImaging

Is telomerase a viable target in cancer?

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