Gene therapy vectors containing CArG elements from the Egr1 gene are activated by neutron irradiation, cisplatin and doxorubicin

Greco, Olga; Powell, T.M.; Marples, Brian; Joiner, Michael C.; Scott, Simon D.

doi:10.1038/sj.cgt.7700834

Cited by 13 publications

(13 citation statements)

References 47 publications

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“…In a series of studies, Weischselbaum and co-workers have exploited the multiple CG-rich so-called CarG-boxes of the Egr1 promoter to prepare a variety of expression vectors that are induced by irradiation. [82][83][84] For example, the radioinducible DNA sequences from the CarG elements of the Egr1 promoter have been cloned upstream of a cDNA encoding TNFa and expressed as an adenoviral construct. Thus, expression of either an anti-Egr1 factor or a general Egr1 is a potential target for gene therapy of prostate cancer V Baron et al proapoptotic factor may be localized by combination with localized (or target directed?)…”

Section: Targeting Egr1 For Gene Therapy Of Prostate Cancermentioning

confidence: 99%

The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFβ1, PTEN, p53, and fibronectin

Bar-On

Adamson

Calogero³

et al. 2005

Cancer Gene Ther

326

281

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Recent studies are reviewed indicating that the transcription factor early growth response-1 (Egr1) is a direct regulator of multiple tumor suppressors including TGFb1, PTEN, p53, and fibronectin. The downstream pathways of these factors display multiple nodes of interaction with each other, suggesting the existence of a functional network of suppressor factors that serve to maintain normal growth regulation and resist the emergence of transformed variants. Paradoxically, Egr1 is oncogenic in prostate cancer. In the majority of these cancers, PTEN or p53 is inactive. It is suggested that these defects in the suppressor network allow for the unopposed induction of TGFb1 and fibronectin, which favor transformation and survival of prostate tumor epithelial cells, and explain the role of Egr1 in prostate cancer. Egr1 is a novel and logical target for intervention by gene therapy methods, and targeting methods are discussed.

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Section: Targeting Egr1 For Gene Therapy Of Prostate Cancermentioning

confidence: 99%

The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFβ1, PTEN, p53, and fibronectin

Bar-On

Adamson

Calogero³

et al. 2005

Cancer Gene Ther

326

281

View full text Add to dashboard Cite

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“…To investigate whether the same mechanism was responsible in the BFTC-905-DOXO-II daughter cell line, we employed the previously described doxorubicin-responsive reporter plasmid pE9ns 2 GFP, which harbours the GFP reporter gene under the control of a synthetic promoter that is strongly activated by intracellular doxorubicin [24,25]. Therefore, cells with overactive ABC efflux transporters display lower GFP fluorescence under doxorubicin treatments.…”

Section: Atypical Mechanism Of Resistance Of Bftc-905-doxo-ii Cellsmentioning

confidence: 99%

“…Transfections were left for 36 h and then split into two 60-mm cell culture dishes. One dish was left with standard growth medium, while the other one was incubated with medium containing 1 μM doxorubicin for 48 h. Green fluorescent protein (GFP) induction was then determined as the fold increase of GFP-positive cells after doxorubicin treatment, as described previously [24,25].…”

Section: Viability and Apoptosis Assaysmentioning

confidence: 99%

Establishment and characterization of a bladder cancer cell line with enhanced doxorubicin resistance by mevalonate pathway activation

et al. 2015

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Resistance to chemotherapy is a major problem in the treatment of urothelial bladder cancer. Several mechanisms have been identified in resistance to doxorubicin by analysis of resistant urothelial carcinoma (UC) cell lines, prominently activation of drug efflux pumps and diminished apoptosis. We have derived a new doxorubicin-resistant cell line from BFTC-905 UC cells, designated BFTC-905-DOXO-II. A doxorubicin-responsive green fluorescent protein (GFP) reporter assay indicated that resistance in BFTC-905-DOXO-II was not due to increased drug efflux pump activity, whereas caspase-3/7 activation was indeed diminished. Gene expression microarray analysis revealed changes in proapoptotic and antiapoptotic genes, but additionally induction of the mevalonate (cholesterol) biosynthetic pathway. Treatment with simvastatin restored sensitivity of BFTC-905-DOXO-II to doxorubicin to that of the parental cell line. Induction of the mevalonate pathway has been reported as a mechanism of chemoresistance in other cancers; this is the first observation in bladder cancer. Combinations of statins with doxorubicin-containing chemotherapy regimens may provide a therapeutic advantage in such cases.

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“…4 In addition, activation of the Egr-1 promoter and specifically the CArG elements has been shown over a broad range of IR doses and also in the response to radioisotopes, neutrons and photons. 6,7,[13][14][15][16][17] The demonstration that IR-induced activation of the CArG elements is blocked by antioxidants supported the generation of reactive oxygen species (ROS), rather than direct damage to DNA, as the upstream signal 5 ( Figure 1). However, other studies have indicated that activation of the Egr-1 promoter in the IR response is mediated, in part, by the release of a diffusible factor into the culture medium.…”

Section: Introductionmentioning

confidence: 99%

Translation of the radio- and chemo-inducible TNFerade vector to the treatment of human cancers

Weichselbaum

Küfe

2009

Cancer Gene Ther

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Radiotherapy is a widely used treatment for localized malignancies that is often delivered in combination with cytotoxic chemotherapeutic agents. The concept that treatment of localized tumors can be improved with a radio-and chemo-inducible gene therapy strategy has been investigated in the laboratory and now translated to the clinic. The TNFerade (Ad.Egr-TNF11D) adenoviral vector was engineered by inserting radio-and chemo-inducible elements from the Egr-1 promoter upstream to a cDNA encoding tumor necrosis factor-a (TNF-a). Transduction of tumor cells with TNFerade and then treatment with radiation or chemotherapy is associated with spatial and temporal control of TNF-a secretion and enhanced antitumor activity. TNFerade has been evaluated in trials for patients with sarcomas, melanomas and cancers of the pancreas, esophagus, rectum and head and neck. If the ongoing phase III trial for pancreatic cancer is successful, TNFerade will likely become the first gene therapy approved for cancer in the United States.

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Gene therapy vectors containing CArG elements from the Egr1 gene are activated by neutron irradiation, cisplatin and doxorubicin

Cited by 13 publications

References 47 publications

The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFβ1, PTEN, p53, and fibronectin

The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFβ1, PTEN, p53, and fibronectin

Establishment and characterization of a bladder cancer cell line with enhanced doxorubicin resistance by mevalonate pathway activation

Translation of the radio- and chemo-inducible TNFerade vector to the treatment of human cancers

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