Targeting gene expression to hypoxic tumor cells

Dachs, Gabi U.; Patterson, Aa.V; Firth, John D.; Ratcliffe, Peter J.; Townsend, K. M. S.; Stratford, I J; Harris, Adrian L.

doi:10.1038/nm0597-515

Cited by 344 publications

(221 citation statements)

References 23 publications

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“…In the first report on hypoxia-regulated gene therapy, a trimer of the murine PGK-1 HRE was inserted in the human 9-27 promoter to regulate the expression of the gene for the enzyme cytosine deaminase (CD; Dachs et al, 1997). This enzyme is not toxic per se, but is able to convert the prodrug 5-fluorocytosine (5-FC) into a cytotoxic agent (gene-directed enzyme/ prodrug therapy, GDEPT; see for a review).…”

Section: Hre-directed Gene Therapymentioning

confidence: 99%

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

Greco

Marples

Joiner

et al. 2003

Journal Cellular Physiology

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Tumor hypoxia has long been recognized as a critical issue in oncology. Resistance of hypoxic areas has been shown to affect treatment outcome after radiation, chemotherapy, and surgery in a number of tumor sites. Two main strategies to overcome tumor hypoxia are to increase the delivery of oxygen (or oxygen-mimetic drugs), or to exploit this unique environmental condition of solid tumors for targeted therapy. The first strategy includes hyperbaric oxygen breathing, the administration of carbogen and nicotinamide, and the delivery of chemical radiosensitizers. In contrast, bioreductive drugs and hypoxia-targeted suicide gene therapy aim at activating cytotoxic agents at the tumor site, while sparing normal tissue from damage. The cellular machinery responds to hypoxia by activating the expression of genes involved in angiogenesis, anaerobic metabolism, vascular permeability, and inflammation. In most cases, transcription is initiated by the binding of the transcription factor hypoxia-inducible factor (HIF) to hypoxia responsive elements (HREs). Hypoxia-targeting for gene therapy has been achieved by utilizing promoters containing HREs, to induce selective and efficient transgene activation at the tumor site. Hypoxia-targeted delivery and prodrug activation may add additional levels of selectivity to the treatment. In this article, the latest developments of cancer gene therapy of the hypoxic environment are discussed, with particular attention to combined protocols with ionizing radiation. Ultimately, it is proposed that by adopting specific transgene activation and molecular amplification systems, resistant hypoxic tumor tissues may be effectively targeted with gene therapy.

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Section: Hre-directed Gene Therapymentioning

confidence: 99%

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

Greco

Marples

Joiner

et al. 2003

Journal Cellular Physiology

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“…The Mf vector system described in this paper was designed to generate activated macrophages (Mf), because the therapeutic gene (IFNg) is an Mf activator and is expressed in an inducible manner in response to molecules, PA or DFX, which have costimulatory activities on Mf. The inducibility by hypoxia of HREcontaining synthetic promoters was previously characterized in vivo 23,24 in vitro, 9,15,25,11,26 and also in Mf. 12,11 New perspectives in the use of hypoxia-sensitive Mf vectors stem from the observation that stimuli other than hypoxia can activate HRE.…”

Section: Activation Of Macrophage Vectors S Pastorino Et Almentioning

confidence: 99%

Picolinic acid- or desferrioxamine-inducible autocrine activation of macrophages engineered to produce IFNγ: an approach for gene therapy

et al. 2004

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Macrophage (Mf)-based vectors are highly mobile cellular shuttles designed to deliver therapeutic genes within the tissues. We engineered a mouse Mf cell line to express the murine interferon-g (IFNg) under the control of an inducible promoter containing the hypoxia-responsive element, which can be triggered by hypoxia and other stimuli. We show that this Mf vector can be induced to produce IFNg under normoxic conditions by stimulation with picolinic acid (PA), a catabolite of tryptophan, or desferrioxamine (DFX), an ironchelating drug. The Mf vector responds to IFNg with the induction of IRF-1 and of other IFNg-inducible genes, the expression of Ia antigens and induction of phagocytic activity.Inducible nitric oxygen synthase gene expression, nitric oxide production, as well as TNFa secretion were enhanced by PA or DFX as the sole stimuli. None of the above responses could be triggered individually by PA or DFX in control, normal Mf, indicating that the Mf vector overcame the need for costimulatory molecules derived from the immune system for its full activation. Furthermore, we demonstrate that extracellular iron can downregulate such response, thereby identifying an additional tool for the fine tuning of the Mf vector response to stimulation.

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“…Characterization of the ERE / HRE promoter and construction of plasmids A cassette containing three copies of the HRE consensus element of the mouse phosphoglycerate kinase -1 (PGK -1 ) 5 H enhancer ( TGTCACGTCCTGCACGAC ) 23 flanked by ClaI sites was subcloned in the ClaI site of the plasmid pERE2pS2CAT. 33 This plasmid contains a portion of the pS2 promoter ( À 90/ + 10 bp), plus two of its EREs.…”

Section: Cell Culturementioning

confidence: 99%

“…The use of this HRE has been reported to direct the expression of therapeutic genes to solid tumors. 23,24 More recently, the HRE was used in combination with cytokineinducible enhancers to direct the expression of genes to endothelial cells. 25 In the present work, our purpose was to develop an artificial hybrid promoter to direct the expression of genes to breast tumors.…”

mentioning

confidence: 99%

Evaluation of a new dual-specificity promoter for selective induction of apoptosis in breast cancer cells

et al. 2001

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The conditional expression of lethal genes in tumor cells is a promising gene therapy approach for the treatment of cancer. The identification of promoters that are preferentially active in cancer cells is the starting point for this strategy. The combination of tissue -specific and tumor -specific elements offers the possibility to artificially develop such promoters. We describe the construction and characterization of a hybrid promoter for transcriptional targeting of breast cancer. In many cases, breast cancer cells retain the expression of estrogen receptors, and most solid tumors suffer from hypoxia as a consequence of their aberrant vascularization. Estrogen response elements and hypoxia -responsive elements were combined to activate transcription in cells that present at least one of these characteristics. When a promoter containing these elements is used to control the expression of the pro -apoptotic gene harakiri, the induction of cell death can be activated by estrogens and hypoxia, and inhibited by antiestrogens such as tamoxifen. Finally, we show evidence that these properties are maintained in the context of an adenoviral vector ( AdEHhrk ). Therefore, infection with this virus preferentially kills estrogen receptor ± positive breast cancer cells, or cells growing under hypoxic conditions. We propose the use of this promoter for transcriptional targeting of breast cancer. Cancer Gene Therapy ( 2001 ) 8, 298 ± 307

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Targeting gene expression to hypoxic tumor cells

Cited by 344 publications

References 23 publications

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

How to overcome (and exploit) tumor hypoxia for targeted gene therapy

Picolinic acid- or desferrioxamine-inducible autocrine activation of macrophages engineered to produce IFNγ: an approach for gene therapy

Evaluation of a new dual-specificity promoter for selective induction of apoptosis in breast cancer cells

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