Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo

White, Christine L.; Menghistu, T; Searle, Peter F.; Bhide, Shreerang A.; Vile, Richard G.; Melcher, Alan; Pandha, H.; Harrington, Kevin

doi:10.1038/sj.gt.3303081

Cited by 15 publications

(15 citation statements)

References 23 publications

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“…Previous studies determined that the HSV1-tk-GCV and CD/5-FC suicide gene therapy systems may improve the sensitivity of tumor cells to radiotherapy, and these systems have demonstrated considerable advantages both in vitro and in vivo (5,18). The NTR/CB1954 gene therapy system is another form of GDEPT and demonstrated an effective tumor reducing treatment on various cells in vivo and in vitro (19,20).…”

Section: Discussionmentioning

confidence: 99%

Combined antitumor activity of the nitroreductase/CB1954 suicide gene system and γ-rays in HeLa cells in vitro

Teng

Yang

et al. 2016

Molecular Medicine Reports

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Escherichia coli nitroreductase (NTR) may convert the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) into a bifunctional alkylating agent, which may lead to DNA crosslinks and the apoptosis of cancer cells. NTR/CB1954 has been demonstrated to be an effective gene therapy in cancer cells. The present study examined whether the NTR/CB1954 suicide gene system had cytotoxic effects on HeLa cells and may improve the radiosensitivity of HeLa cells to γ-rays. It was observed that the NTR/CB1954 suicide gene system exerted marked cytotoxic effects on HeLa cells. The combined therapeutic effects of NTR/CB1954 and γ-rays on HeLa cells demonstrated a synergistic effect. CB1954 at concentrations of 12.5 and 25 µmol/l increased the sensitization enhancement ratio of HeLa cells to 1.54 and 1.66, respectively. Therefore, when compared with monotherapy, the combined therapy of NTR/CB1954 and γ-rays may increase the apoptotic rate and enhance the radiosensitivity of HeLa cells. The combined therapy of γ-ray radiation and the NTR/CB1954 suicide gene system may be a novel and potent therapeutic method for the treatment of cervical carcinoma.

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Section: Discussionmentioning

confidence: 99%

Combined antitumor activity of the nitroreductase/CB1954 suicide gene system and γ-rays in HeLa cells in vitro

Teng

Yang

et al. 2016

Molecular Medicine Reports

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“…[31][32][33][34][35] Shibata et al 8 used the NTR/CB1954 system in a xenograft model with a VEGF HRE to examine the effects on hypoxia. The NTR gene was stably transfected into fibrosarcoma cells before tumor formation in mice.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated hypoxia-targeted gene therapy using HSV thymidine kinase and bacterial nitroreductase prodrug-activating genes in vitro and in vivo

et al. 2011

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Hypoxia is an important factor in tumor growth. It is associated with resistance to conventional anticancer treatments. Gene therapy targeting hypoxic tumor cells therefore has the potential to enhance the efficacy of treatment of solid tumors. Transfection of a panel of tumor cell lines with plasmid constructs containing hypoxia-responsive promoter elements from the genes, vascular endothelial growth factor (VEGF) and erythropoietin, linked to the minimal cytomegalovirus (mCMV) or minimal interleukin-2 (mIL-2) promoters showed optimum hypoxia-inducible luciferase reporter gene expression with five repeats of VEGF hypoxic-response element linked to the mCMV promoter. Adenoviral vectors using this hypoxia-inducible promoter to drive therapeutic transgenes produced hypoxia-specific cell kill of HT1080 and HCT116 cells in the presence of prodrug with both herpes simplex virus thymidine kinase/ganciclovir and nitroreductase (NTR)/CB1954 prodrug-activating systems. Significant cytotoxic effects were also observed in patient-derived human ovarian cancer cells. The NTR/CB1954 system provided more readily controllable transgene expression and so was used for in vivo experiments of human HCT116 xenografts in nude mice. Subjects treated intratumorally with Ad-VEGFmCMV-NTR and intraperitoneal injection of CB1954 demonstrated a statistically significant reduction in tumor growth. Immunohistochemistry of treated xenografts showed a good correlation between transgene expression and hypoxic areas. Further investigation of these hypoxia-inducible adenoviral vectors, alone or in combination with existing modalities of cancer therapy, may aid in the future development of successful Gene-Directed Enzyme Prodrug Therapy systems, which are much needed for targeting solid tumors.

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“…The combination of radiation and reovirus for paediatric sarcomas was also shown to cause significant tumour regression in both RH30 and SKES xenografts with enhanced efficacy when compared to the individual treatments [55] . Other oncolytic viral therapies, for example adenovirus, are already under evaluation in combination with radiotherapy and have shown increased in vitro and in vivo efficacy with no additional side effects [56,57] .…”

Section: Reovirus In Combination With Radiationmentioning

confidence: 99%

Reovirus therapy in cancer: has the orphan virus found a home?

Yap

Brunetto

Pandha

et al. 2008

Expert Opinion on Investigational Drugs

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Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo

Cited by 15 publications

References 23 publications

Combined antitumor activity of the nitroreductase/CB1954 suicide gene system and γ-rays in HeLa cells in vitro

Combined antitumor activity of the nitroreductase/CB1954 suicide gene system and γ-rays in HeLa cells in vitro

Adenovirus-mediated hypoxia-targeted gene therapy using HSV thymidine kinase and bacterial nitroreductase prodrug-activating genes in vitro and in vivo

Reovirus therapy in cancer: has the orphan virus found a home?

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