p21(WAF1)-mediated transcriptional targeting of inducible nitric oxide synthase gene therapy sensitizes tumours to fractionated radiotherapy

McCarthy, Helen; Worthington, Jenny; Barrett, E.; Cosimo, Emilio; Boyd, Marie; Mairs, Robert J.; Ward, Claire; McKeown, Stephanie; Hirst, DG; Robson, Tracy

doi:10.1038/sj.gt.3302871

Cited by 41 publications

(45 citation statements)

References 40 publications

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“…Plausible mechanisms for this effect being the enhanced formation and reduced repair of radiation-induced DNA strand breaks and inhibition of the radioresistant hypoxia response. These data and that from other studies [40] lend support to future clinical trials of NO-sulindac plus radiotherapy in men with prostate cancer. Ultimately, NO-NSAIDs and other NO-donors may be useful as neoadjuvant and concurrent treatments for men undergoing radiotherapy for prostate cancer.…”

Section: Discussionsupporting

confidence: 72%

DNA strand breaks and hypoxia response inhibition mediate the radiosensitisation effect of nitric oxide donors on prostate cancer under varying oxygen conditions

Stewart

Nanda

Katz

et al. 2011

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. *ManuscriptPage 2 of 32 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

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Section: Discussionsupporting

confidence: 72%

DNA strand breaks and hypoxia response inhibition mediate the radiosensitisation effect of nitric oxide donors on prostate cancer under varying oxygen conditions

Stewart

Nanda

Katz

et al. 2011

Biochemical Pharmacology

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“…Moreover, a clinically relevant schedule of p21((WAF1))-driven iNOS gene therapy resulted in significant sensitization of both p53 wild-type RIF-1 tumors and p53 mutant HT29 tumors to fractionated radiotherapy. 41 MCF-7 cells transduced with WAF-1-driven HSVtk gene in an rAAV vector were significantly sensitized to repetitive treatment with low dose radiation (1 Gy) in the presence of the prodrug ganciclovir (GCV). 31 Wild type Erg-1 gene promoter.…”

Section: Radiation-induced Cancer Gene Therapy Strategiesmentioning

confidence: 99%

Radiation to control transgene expression in tumors

Marignol¹,

Coffey²,

Hollywood³

et al. 2007

Cancer Biology & Therapy

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Significant evidence has accumulated indicating that certain genes are induced by ionising radiation. An implication of this observation is that their promoter regions include radiation-responsive sequences. These sequences have been isolated in the promoter of several genes including Erg-1, p 21/WAF-1 , GADD45a and t-PA. The mechanism by which radiation induces gene expression remains unclear but involves putative binding sites for selected transcription factors and/or p53. Consensus CC(A/T) 6 GG sequences have been localized in the Erg-1 promoter and are referred to as serum response elements or CArG elements. The tandem combination of CArG elements has been shown to improve gene expression levels, with a 9-copy motif conferring maximum inducibility. The response of these genes to ionising radiation appears to follow a sigmoid relationship with time and dose. Therapeutic induction of suicide genes and significant cytotoxicity can be achieved at clinically relevant x-rays doses both in vitro and in vivo but was found to be cell-type dependent. Radiation-inducible gene therapy can be potentially enhanced by exploiting hypoxia through the inclusion of hypoxia-response element motifs in the expression cassette, the use of the anaerobic bacteria or the use of neutron irradiation. These results are encouraging and provide significant evidence that gene therapy targeted to the radiation field is a reasonably attractive therapeutic option and could help overcome hypoxic radioresistant tumors.

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“…The induction of early response by ionizing radiation involves the expression of immediate early genes that code for transcription factors (e.g., Fos, Jun, AP-1, NF-κB) as well as cytokines and growth factors [e.g., early growth response factor-1 (EGR-1)] (6,7). Among the genes whose expressions are induced by ionizing radiation, the promoters of EGR-1 (8), p21 (9) and others (10,11) have been successfully used to control gene expression by ionizing radiation in both in vitro and in vivo experiments. Functional analysis of the EGR-1 gene demonstrates that the DNA sequences that drive the radiation-inducible response are located in the enhancer region of the consensus sequence CC(A/T)6GG, also known as CArG elements.…”

Section: Introductionmentioning

confidence: 99%

Radiation-inducible silencing of uPA and uPAR in vitro and in vivo in meningioma

Rao¹

2010

Int J Oncol

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Abstract. Stereospecific radiation treatment offers a distinct opportunity for temporal and spatial regulation of gene expression at tumor sites by means of inducible promoters. To this end, a plasmid, pCArG-U2, was constructed by incorporating nine CArG elements (in tandem) of EGR1 gene upstream to uPA and uPAR siRNA oligonucleotides in a pCi-neo vector. Radiation-induced siRNA expression was detected in a meningioma cell line (IOMM-Lee). Immunoblotting and RT-PCR analyses confirmed downregulation of uPA and uPAR. A similar effect was observed in transfected cells followed by H 2 O 2 treatment. Moreover, pre-treatment of transfected cells with N-acetyl L-cysteine blocked the silencing of uPA and uPAR, which further confirmed the oxidative damage-mediated downregulation. Cell proliferation assays and Western blot analysis for apoptotic molecules confirmed cell death in a radiation-inducible fashion. Migration and Matrigel invasion assays also revealed a marked decrease in migration and invasion. Immunocytochemistry showed a marked decrease in uPA and uPAR levels in transfected and irradiated cells. H&E staining revealed a decrease in the preestablished tumor volume among the animals treated with pCArG-U2 and radiation. Immunohistochemistry of the brain sections established with intracranial tumors also revealed a marked decrease in uPA and uPAR in a radiation-inducible fashion. Taken together, our data suggest pCArG-U2 as a suitable candidate for radiation-inducible gene therapy.

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p21(WAF1)-mediated transcriptional targeting of inducible nitric oxide synthase gene therapy sensitizes tumours to fractionated radiotherapy

Cited by 41 publications

References 40 publications

DNA strand breaks and hypoxia response inhibition mediate the radiosensitisation effect of nitric oxide donors on prostate cancer under varying oxygen conditions

DNA strand breaks and hypoxia response inhibition mediate the radiosensitisation effect of nitric oxide donors on prostate cancer under varying oxygen conditions

Radiation to control transgene expression in tumors

Radiation-inducible silencing of uPA and uPAR in vitro and in vivo in meningioma

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