Enhanced efficacy of Escherichia coli nitroreductase/CB1954 prodrug activation gene therapy using an E1B-55K-deleted oncolytic adenovirus vector

Mj, Chen; Nk, Green; Reynolds, GM; Flavell, JR; Mautner, Vivien; Dj, Kerr; Lw, Young; Pf, Searle

doi:10.1038/sj.gt.3302271

Cited by 42 publications

(35 citation statements)

References 34 publications

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“…Chen et al 84 reported that direct intratumor injection (2 Â 10 8 PFU per dose; qdx5) of the E1B-deleted CRAd CMV-NTR in SW480 xenografts provided a 36-day improvement in IMS that was extended by just 3 days on addition of CB 1954 (25 mg kg À1 per dose; IP, qdx4). Lukashev et al 62 subsequently compared the efficacy of CMV-NTR with that of a Tcf-regulated CRAd harboring an L5-located NTR optimized for CB 1954 metabolism (Tcf-NTR).…”

Section: Discussionmentioning

confidence: 99%

The nitroreductase prodrug SN 28343 enhances the potency of systemically administered armed oncolytic adenovirus ONYX-411NTR

Singleton

Bai

et al. 2007

Cancer Gene Ther

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Section: Discussionmentioning

confidence: 99%

The nitroreductase prodrug SN 28343 enhances the potency of systemically administered armed oncolytic adenovirus ONYX-411NTR

Singleton

Bai

et al. 2007

Cancer Gene Ther

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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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“…3,4 Furthermore, in an effort to increase transgene delivery we have constructed a conditionally replicating oncolytic E1B-attenuated adenovirus to deliver NR with promising preclinical results. 5 It is known that wild type and attenuated adenovirus can interact with cellular signalling pathways in a range of human cell types as part of the infective life cycle. For example, both the NF-kB and MAP kinase pathways are reported to be activated by adenovirus infection of respiratory epithelium, endothelial cells, hepatocytes and antigen-presenting cells.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of NF-κB enhances the cytotoxicity of virus-directed enzyme prodrug therapy and oncolytic adenovirus cancer gene therapy

et al. 2005

Gene Ther

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Virus-directed enzyme prodrug therapy utilizing the bacterial enzyme nitroreductase delivered by a replication-defective adenovirus vector to activate the prodrug CB1954 is a promising strategy currently undergoing clinical trials in patients with a range of cancers. Similarly, selectively replicating oncolytic adenoviruses are entering clinical trials. An understanding of interactions between vector and target cell are critical to the development of these strategies. We demonstrate that adenovirus vectors activate cellular pathways that promote cell survival in an NF-kB-dependent manner, and consequently have a negative effect on the efficacy of cell killing induced by cancer gene therapy strategies. This provides a potential therapeutic target to enhance the cytotoxicity of these approaches.

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Enhanced efficacy of Escherichia coli nitroreductase/CB1954 prodrug activation gene therapy using an E1B-55K-deleted oncolytic adenovirus vector

Cited by 42 publications

References 34 publications

The nitroreductase prodrug SN 28343 enhances the potency of systemically administered armed oncolytic adenovirus ONYX-411NTR

The nitroreductase prodrug SN 28343 enhances the potency of systemically administered armed oncolytic adenovirus ONYX-411NTR

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

Inhibition of NF-κB enhances the cytotoxicity of virus-directed enzyme prodrug therapy and oncolytic adenovirus cancer gene therapy

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