Sensitisation of human carcinoma cells to the prodrug CB1954 by adenovirus vector-mediated expression ofE. coli nitroreductase

Weedon, Sarah J.; Green, Nicola K.; McNeish, Iain A.; Gilligan, Moira G.; Mautner, Vivien; Wrighton, Christopher J.; Mountain, Andrew; Young, Lawrence S.; Kerr, David; Searle, Peter F.

doi:10.1002/(sici)1097-0215(20000615)86:6<848::aid-ijc14>3.0.co;2-b

Cited by 73 publications

(62 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This utilises an adenovirus delivered enzyme, nitroreductase (NR), to catalyse the conversion of a relatively nontoxic prodrug (CB1954) into an extremely potent DNA cross-linking agent. Preclinical studies have shown that adenoviral delivery of NR to a range of human cancer cell lines sensitises them to CB1954 by 500 -2000-fold compared to the parental cell line (Weedon et al, 2000). Further, in an in vivo xenograft model of peritoneal pancreatic cancer (Suit 2), a doubling in median survival was seen in mice treated with virus and CB1954 compared to controls (Po0.0001) (Weedon et al, 2000).…”

mentioning

confidence: 99%

Mechanism of cell death induced by the novel enzyme-prodrug combination, nitroreductase/CB1954, and identification of synergism with 5-fluorouracil

et al. 2003

View full text Add to dashboard Cite

Virus-directed enzyme prodrug therapy (VDEPT) utilising 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. An understanding of the mechanism of tumour cell death induced by activated CB1954 will facilitate this clinical development. Here, we report that activated CB1954 kills cells predominantly by caspase-dependent apoptosis. This may have important implications for the generation of immune-mediated bystander effects. Further, the use of a replication-defective adenovirus vector to deliver nitroreductase may negatively affect cellular apoptotic pathways stimulated by activated CB1954. Finally, examination of nitroreductase/CB1954 in combination with conventional chemotherapy reveals a synergistic interaction with 5-fluorouracil. These data will facilitate the further development and future clinical trial design of this novel therapy.

show abstract

mentioning

confidence: 99%

Mechanism of cell death induced by the novel enzyme-prodrug combination, nitroreductase/CB1954, and identification of synergism with 5-fluorouracil

et al. 2003

View full text Add to dashboard Cite

show abstract

“…The IC 50 values observed with both HSVtk/GCV and NTR/ CB1954 are comparable to values obtained in previous studies. 18,19 Cytotoxicity of adenovirus-delivered prodrug enzyme systems in human primary ovarian cancer cells Primary ovarian cancer cells taken directly from patient ascites are not easily transduced by adenovirus. However, an early adaptation to culture is to become adherent, with consequent alterations in phenotype, which results in enhanced infectivity.…”

Section: Comparison Of Vegf and Epo Hresmentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…It was shown that NTR-expressing cell lines are 500 -2000-fold more sensitive to CB1954 than parental cell lines (Green et al, 1997;McNeish et al, 1998). Importantly, a strong bystander effect operates and, with only 5% of cells transfected, high levels of total cell kill (490%) were observed (McNeish et al, 1998) with similar efficacy in vivo (Weedon et al, 2000).…”

Section: XVmentioning

confidence: 99%

Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

et al. 2003

View full text Add to dashboard Cite

Sensitisation of human carcinoma cells to the prodrug CB1954 by adenovirus vector-mediated expression ofE. coli nitroreductase

Cited by 73 publications

References 15 publications

Mechanism of cell death induced by the novel enzyme-prodrug combination, nitroreductase/CB1954, and identification of synergism with 5-fluorouracil

Mechanism of cell death induced by the novel enzyme-prodrug combination, nitroreductase/CB1954, and identification of synergism with 5-fluorouracil

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

Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

Contact Info

Product

Resources

About