Selective cell ablation in transgenic mice expressing E. coli nitroreductase

Clark, Alicia; Iwobi, M; Cui, Wei; Crompton, M. R.; Harold, Graham; Hobbs, Steve; Kamalati, Tahereh; Knox, Richard J.; Neil, C.; Yull, Fiona E.; Gusterson, Barry A.

doi:10.1038/sj.gt.3300367

Cited by 75 publications

(84 citation statements)

References 7 publications

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“…The results of histological examination during tumor regression were consistent with previous reports 12,13 that the ntr/CB1954 system kills cells through induction of apoptosis. Our results also showed, however, that apoptotic cell death was followed by necrosis at later timepoints, suggesting that the macrophage infiltration Figure 9.…”

Section: Discussionsupporting

confidence: 91%

“…Cellular thioesters such as acetyl coenzyme A subsequently convert the latter into a powerful bifunctional alkylating agent 10 that can kill both proliferating and nonproliferating cells. 11,12 At the molecular level, this cell killing involves induction of interstrand DNA cross-links and apoptosis. 10,12,13 Tumor cell lines expressing NTR in vitro after stable transfection with the ntr gene are usually at least a hundred times more sensitive to CB1954 than untransfected cells.…”

mentioning

confidence: 99%

“…11,12 At the molecular level, this cell killing involves induction of interstrand DNA cross-links and apoptosis. 10,12,13 Tumor cell lines expressing NTR in vitro after stable transfection with the ntr gene are usually at least a hundred times more sensitive to CB1954 than untransfected cells. 14,15 Furthermore, bystander cell killing has been clearly demonstrated for tumor cells in vitro.…”

mentioning

confidence: 99%

“…14 -16 Expression of NTR restricted either to the thymus and spleen (using the CD2 locus control region) or to the mammary gland (using the ␤-lactoglobulin promoter) in transgenic mice has been used to investigate cell killing in vivo with the ntr/CB1954 system. 12,13 Both studies demonstrated selective cell killing after CB1954 administration but gave little information regarding bystander killing effects in vivo.…”

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confidence: 99%

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Expression of Escherichia coli B nitroreductase in established human tumor xenografts in mice results in potent antitumoral and bystander effects upon systemic administration of the prodrug CB1954

Hulme²,

et al. 2000

Cancer Gene Ther

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Expression of the Escherichia coli enzyme nitroreductase (NTR) in mammalian cells enables them to activate the prodrug 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB1954), leading to interstrand DNA cross-linking and apoptosis in both proliferating and quiescent cells. In the work reported here, we used human hepatocellular carcinoma and squamous carcinoma cell lines constitutively expressing NTR to demonstrate that the ntr/CB1954 system results in potent, long-lasting antitumoral effects in mice. We also demonstrate that this enzyme/prodrug combination results in antitumoral effects in vivo when only a minority of tumor cells express the enzyme, using either cells constitutively expressing NTR or ntr gene delivery in situ. Cancer Gene Therapy (2000) 7, 721-731

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Expression of Escherichia coli B nitroreductase in established human tumor xenografts in mice results in potent antitumoral and bystander effects upon systemic administration of the prodrug CB1954

Hulme²,

et al. 2000

Cancer Gene Ther

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“…7 Furthermore, cells can be rendered susceptible to prodrugs by expression of transgenes encoding enzymes that will generate from them cytotoxic products. 8,9 An alternative approach to inducible lineage ablation uses transgenic expression of receptor for toxins, which the organism is naturally resistant to. In this method, the expressed gene product itself is not harmful, yet sensitizes to an applicable toxin, leading to the specific death of the cell type, which expresses the receptor.…”

Section: Constitutive and Conditional Cell Ablationmentioning

confidence: 99%

Probing in vivo dendritic cell functions by conditional cell ablation

Sapoznikov

2008

Immunol Cell Biol

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Dendritic cells (DCs) play a central role in T-cell activation and the control of the inherent autoreactivity of the T-cell compartment. Pleiotropic DC functions are likely associated with discrete DC subsets. However, the latter remain largely defined by phenotype and unique anatomic location, rather than function. The investigation of DC involvement in complex phenomena that rely on multicellular interactions, such as immuno-stimulation and tolerization calls for an assessment of DC functions within physiological context. Given the highly dynamic DC compartment, the method of choice to study in vivo DC functions is their conditional ablation in the intact organism. Here, we summarize the recent progress in this field highlighting pitfalls and prospects of the approach.

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