A novel single tetracycline-regulative adenoviral vector for tumor-specific Bax gene expression and cell killing in vitro and in vivo

Gu, Jian; Zhang, Youmin; Huang, Xuefeng; Lin, Tong; Yin, Min; Xu, Kai; Ji, Lin; Roth, Jack A.; Fang, Bingliang

doi:10.1038/sj.onc.1205582

Cited by 50 publications

(36 citation statements)

References 19 publications

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“…Next, we asked whether the circuit (SC-2) can selectively induce apoptosis of bladder cancer cell by regulating expression of human Bax gene, which is a pro-apoptotic gene 14 . As previously reported, Bax protein is a hallmark of cell apoptosis and has the ability to induce apoptosis in a wide variety of cells.…”

Section: Resultsmentioning

confidence: 99%

Synthesizing AND gate genetic circuits based on CRISPR-Cas9 for identification of bladder cancer cells

et al. 2014

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The conventional strategy for cancer gene therapy offers limited control of specificity and efficacy. A possible way to overcome these limitations is to construct logic circuits. Here we present modular AND gate circuits based on CRISPR-Cas9 system. The circuits integrate cellular information from two promoters as inputs and activate the output gene only when both inputs are active in the tested cell lines. Using the luciferase reporter as the output gene, we show that the circuit specifically detects bladder cancer cells and significantly enhances luciferase expression in comparison to the human telomerase reverse transcriptase-renilla luciferase construct. We also test the modularity of the design by replacing the output with other cellular functional genes including hBAX, p21 and E-cadherin. The circuits effectively inhibit bladder cancer cell growth, induce apoptosis and decrease cell motility by regulating the corresponding gene. This approach provides a synthetic biology platform for targeting and controlling bladder cancer cells in vitro.

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Section: Resultsmentioning

confidence: 99%

Synthesizing AND gate genetic circuits based on CRISPR-Cas9 for identification of bladder cancer cells

et al. 2014

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“…Moreover, other groups have used MOI as high as 2000-3000 to obtain therapeutic effects using adenovirus and tissue-specific promoters. 31,32 To correlate the effect of gas1 expression on cell viability we measured the release of LDH from glioma-transduced cells, as an indicator of cell death. Figure 2c shows a significant increase of LDH release from AdSGas1-transduced C6 and U373 cells at 1000 MOI, compared with AdSLacZ.…”

Section: Resultsmentioning

confidence: 99%

Targeted-simultaneous expression of Gas1 and p53 using a bicistronic adenoviral vector in gliomas

et al. 2007

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The targeted expression of transgenes is one of the principal goals of gene therapy, and it is particularly relevant for the treatment of brain tumors. In this study, we examined the effect of the overexpression of human gas1 (growth arrest specific 1) and human p53 cDNAs, both under the transcriptional control of a promoter of the human glial fibrillary acidic protein (gfa2), employing adenoviral expression vectors, in glioma cells. We showed that the targeted overexpression of gas1 and p53 (AdSGas1 and AdSp53, respectively) in rat glioma cells (C6) reduced the number of viable cells and induced apoptosis. Moreover, the adenovirally targeted expression of these genes also reduced tumor growth in vivo. Unexpectedly, there was no additive effect when both gas1 and p53 were simultaneously expressed in the same cells using a bicistronic adenoviral vector. We suggest that Gas1 does not act in combination with p53 in the C6 and U373 glioma cell lines, inducing apoptosis and cell cycle arrest. Our results indicate that the targeted expression of tumor suppressor genes (gas1 and p53) regulated by the gfa2 promoter, together with adenoviral vectors may provide an interesting approach for adjuvant selective glioma gene therapy.

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“…Telomerase is a ribonucleoprotein complex responsible for the addition of TTAGGG repeats to the telomeric ends of chromosomes (Greider and Blackburn, 1985;Collins and Mitchell, 2002), and contains the enzymatic subunit human telomerase reverse transcriptase (hTERT) (Nakamura et al, 1997). The hTERT proximal promoter can be used as a molecular switch for the selective expression of target genes in tumor cells (Koga et al, 2000;Komata et al, 2001;Gu et al, 2000Gu et al, , 2002, since almost all advanced human cancer cells express telomerase and most normal cells do not (Kim et al, 1994;Shay and Wright, 1996). Genetically modified adenoviruses have emerged as a new biological anticancer agent (McCormick, 2001;Fang and Roth, 2003).…”

Section: Introductionmentioning

confidence: 99%

Enhanced oncolysis by a tropism-modified telomerase-specific replication-selective adenoviral agent OBP-405 (‘Telomelysin-RGD’)

et al. 2005

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Replication-competent oncolytic viruses are being developed for human cancer therapy. We previously reported that an attenuated adenovirus (OBP-301, 'Telomelysin'), in which the hTERT promoter element drives expression of E1A and E1B genes linked with an IRES, could replicate in cancer cells, and causes selective lysis of cancer cells. We further constructed OBP-405 ('Telomelysin-RGD') that contains an RGD motif in the HI loop of the fiber knob. We examined whether OBP-405 could be effective in overcoming the limitations of OBP-301, specifically their inefficient infection into cells lacking the primary receptor, the coxsackievirus and adenovirus receptor (CAR). By flow cytometric analysis, H1299 (lung) and SW620 (colorectal) tumor cells showed high levels of CAR expression, whereas LN444 (glioblastoma), LNZ308 (glioblastoma), and H1299-R5 (lung) tumor cells were negative for CAR expression. A quantitative realtime PCR analysis demonstrated that fiber-modified OBP-405 infected more efficiently than OBP-301, although the intracellular replication rate of both viruses was consistent. The comparative antitumor effect of fibermodified OBP-405 and unmodified OBP-301 for human cancer cells was evaluated in vitro by XTT assay as well as in vivo by using athymic mice carrying xenografts. OBP-405 had a profound oncolytic effect on human cancer cell lines compared to OBP-301, in particular on cells with low CAR expression. Intratumoral injection of 10 7 plaque-forming units of OBP-405 into CAR-negative H1299-R5 lung tumor xenografts in nu/nu mice resulted in a significant inhibition of tumor growth and long-term survival in all treated mice. Moreover, selective replication of OBP-405 in the distant, uninjected H1299-R5 tumors was demonstrated. Our results suggest that fiber-modified replication-competent adenovirus OBP-405 exhibits a broad target range by increasing infection efficiency, an outcome that has important implications for the treatment of human cancers.

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A novel single tetracycline-regulative adenoviral vector for tumor-specific Bax gene expression and cell killing in vitro and in vivo

Cited by 50 publications

References 19 publications

Synthesizing AND gate genetic circuits based on CRISPR-Cas9 for identification of bladder cancer cells

Synthesizing AND gate genetic circuits based on CRISPR-Cas9 for identification of bladder cancer cells

Targeted-simultaneous expression of Gas1 and p53 using a bicistronic adenoviral vector in gliomas

Enhanced oncolysis by a tropism-modified telomerase-specific replication-selective adenoviral agent OBP-405 (‘Telomelysin-RGD’)

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