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

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

doi:10.1002/jcp.10374

Cited by 65 publications

(50 citation statements)

References 152 publications

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“…Moreover, targeting gene expression to the hypoxic regions of solid tumors will allow the use of lower doses of the vector and decrease the risk of side effects. 26,27 In this respect, the successful performance of the E-M-H vector in LLC1 carcinoma cells should be noted.…”

Section: Discussionmentioning

confidence: 99%

A novel chimeric promoter that is highly responsive to hypoxia and metals

et al. 2006

Gene Ther

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To develop a potent hypoxia-inducible promoter, we evaluated the usefulness of chimeric combinations of the (Egr-1)-binding site (EBS) from the Egr-1 gene, the metal-response element (MRE) from the metallothionein gene, and the hypoxia-response element (HRE) from the phosphoglycerate kinase 1 gene. In transient transfection assays, combining three copies of HRE (3 Â HRE) with either EBS or MRE significantly increased hypoxia responsiveness. When a three-enhancer combination was tested, the EBS-MRE-3 Â HRE (E-M-H) gave a hypoxia induction ratio of 69. The expression induced from E-M-H-pGL3 was 2.4-fold higher than that induced from H-pGL3 and even surpassed the expression from a human cytomegalovirus promoter-driven vector. The high inducibility of E-M-H was confirmed by validation studies in different cells and by expressing other cDNAs. Gel shift assays together with functional overexpression studies suggested that increased levels of hypoxiainducible factor 1a, metal transcription factor-1 and Egr-1 may be associated with the high inducibility of the E-M-H chimeric promoter. E-M-H was also induced by hypoxia mimetics such as Co 2+ and deferoxamine (DFX) and by hydrogen peroxide. Gene expression from the E-M-H was reversible as shown by the reduced expression of the transgene upon removal of inducers such as hypoxia and DFX. In vivo evaluation of the E-M-H in ischemic muscle revealed that erythropoietin secretion and luciferase and LacZ expression were significantly higher in the E-M-H group than in a control or H group. With its high induction capacity and versatile means of modulation, this novel chimeric promoter should find wide application in the treatment of ischemic diseases and cancer.

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Section: Discussionmentioning

confidence: 99%

A novel chimeric promoter that is highly responsive to hypoxia and metals

et al. 2006

Gene Ther

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“…The critical changes in the cellular microenvironment are due to an inadequate oxygen supply and the resultant hypoxia (2). The hypoxic tumor environment results in aggressive and metastatic cancer phenotypes that are associated with resistance to radiation therapy, chemotherapy, and a poor treatment outcome (3,4). Hypoxia detected in the central regions of solid tumors can be a leading cause of angiogenesis, a fundamental determinant of malignant tumor progression, by activating the expression of angiogenic factors (5,6).…”

Section: Introductionmentioning

confidence: 99%

Curcumin inhibits hypoxia-induced angiogenesis via down-regulation of HIF-1

Bae

Kim²,

Jeong³

et al. 2006

Oncol Rep

106

103

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Abstract. Hypoxia-inducible factor-1 (HIF-1) has a central role in cellular responses to hypoxia, including the transcriptional activation of a number of genes involved in angiogenesis in tumors. We found that curcumin, a natural, biologically active compound isolated from the commonly used spice turmeric, significantly decreases hypoxia-induced HIF-1· protein levels in HepG2 hepatocellular carcinoma cells. Moreover, curcumin suppressed the transcriptional activity of HIF-1 under hypoxia, leading to a decrease in the expression of vascular endothelial growth factor (VEGF), a major HIF-1 target angiogenic factor. Curcumin also blocked hypoxia-stimulated angiogenesis in vitro and down-regulated HIF-1· and VEGF expression in vascular endothelial cells. These findings suggest that curcumin may play pivotal roles in tumor suppression via the inhibition of HIF-1·-mediated angiogenesis.

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“…HSVtk/GCV and NTR/CB1954 have been widely used in a number of cytotoxic gene therapy studies, including therapies targeting hypoxia. [21][22][23][24] Only a few studies have compared both HSVtk and NTR systems in parallel, but none of these comparisons has been under hypoxic conditions with different transcriptional regulation. In one study, HSVtk/GCV showed the widest therapeutic index, whereas NTR/CB1954 demonstrated a stronger bystander effect in a retroviral vector.…”

Section: Discussionmentioning

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

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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.

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

Cited by 65 publications

References 152 publications

A novel chimeric promoter that is highly responsive to hypoxia and metals

A novel chimeric promoter that is highly responsive to hypoxia and metals

Curcumin inhibits hypoxia-induced angiogenesis via down-regulation of HIF-1

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

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