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

Harvey, Tracey J.; Hennig, I.; Shnyder, Steve D.; Cooper, Patricia A.; Ingram, Nicola; Hall, G. D.; Selby, Peter J.; Chester, John D.

doi:10.1038/cgt.2011.43

Cited by 20 publications

(12 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The 5HRE element has previously been used as an enhancer to utilize the hypoxic microenvironment (39). Harvey et al (40) developed a hypoxia-targeted gene therapy strategy using the herpes simplex virus thymidine kinase and bacterial nitroreductase pro-drug-activating genes and showed that 5HRE linked to the CMV minimal promoter could induce optimum luciferase reporter gene expression. In our previous study, gene therapy vectors under the control of 5HRE and a minimal tumor specific promoter also displayed optimal activation at a low oxygen tension in hepatoma and gastric cancer cells (25,41).…”

Section: Discussionmentioning

confidence: 99%

Targeted CDX2 expression inhibits aggressive phenotypes of colon cancer cells in vitro and in vivo

Zheng

He²,

et al. 2017

International Journal of Oncology

View full text Add to dashboard Cite

Loss of caudal type homeobox 2 (CDX2) is associated with the development of human colorectal cancer, while human telomerase reverse transcriptase (hTERT) frequently occurs in variety of human cancers. We investigated the effects of restoration of CDX2 expression using a hypoxia-inducible hTERT promoter-driven vector (pLVX-5HRE-hTERTp-CDX2-3FLAG) on colon cancer cell viability, cell cycle distribution, apoptosis, colony formation, invasion ability and xenograft tumor growth in nude mice. CDX2 overexpression significantly inhibited viability, colony formation, and the invasion and migration ability of LoVo cells, and induced cell cycle arrest and apoptosis in vitro, especially under hypoxic culture conditions. Overexpression of CDX2 under normoxic conditions significantly suppressed the expression of TGF-β, cyclin D1, uPA, MMP-9, MMP-2, and Bcl-2, and stimulated the expression of collagen IV, laminin-1, and Bax. Overexpression of CDX2 reduced colon cancer xenograft tumor formation in nude mice which was associated with downregulation of Ki-67. In conclusion, overexpression of CDX2 using a hypoxia-inducible hTERT promoter-driven vector suppressed malignant progression of colon cancer cells in vitro and in vivo. These results suggest that pLVX-5HRE-hTERTp-CDX2-3FLAG gene therapy may be a promising novel approach to treat colon cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Targeted CDX2 expression inhibits aggressive phenotypes of colon cancer cells in vitro and in vivo

Zheng

He²,

et al. 2017

International Journal of Oncology

View full text Add to dashboard Cite

show abstract

“…This is a clear limitation of this method for regenerative research; it is only effective for eliminating proliferating cell populations. However, therapeutically, this has advantages within the realm of chemotherapy [31]. Similarly, this ‘limitation’ could be leveraged to test the plasticity of regenerative responses regarding the relative roles of proliferative and non-proliferative (i.e., transdifferentiation) mechanisms of cell replacement.…”

Section: Cell-specific Ablation Systemsmentioning

confidence: 99%

The nitroreductase system of inducible targeted ablation facilitates cell-specific regenerative studies in zebrafish

White

Mumm

2013

Methods

View full text Add to dashboard Cite

At the turn of the 20th century, classical regenerative biology – the study of organismal/tissue/limb regeneration in animals such as crayfish, snails, and planaria – garnered much attention. However, scientific luminaries such as Thomas Hunt Morgan eventually turned to other fields after concluding that inquiries into regenerative mechanisms were largely intractable beyond observational intrigues. The field of regeneration has enjoyed a resurgence in research activity at the turn of the 21st century, in large part due to “the promise” of cultured stem cells regarding reparative therapeutic approaches. Additionally, genomics-based methods that allow sophisticated genetic/molecular manipulations to be carried out in nearly any species have extended organismal regenerative biology well beyond observational limits. Throughout its history, complex paradigms such as limb regeneration – involving multiple tissue/cell types, thus, potentially multiple stem cell subtypes – have predominated the regenerative biology field. Conversely, cellular regeneration – the replacement of specific cell types – has been studied from only a few perspectives (predominantly muscle and mechanosensory hair cells). Yet, many of the degenerative diseases that regenerative biology hopes to address involve the loss of individual cell types; thus, a primary emphasis of the embryonic/induced stem cell field is defining culture conditions which promote cell-specific differentiation. Here we will discuss recent methodological approaches that promote the study of cell-specific regeneration. Such paradigms can reveal how the differentiation of specific cell types and regenerative potential of discrete stem cell niches are regulated. In particular, we will focus on how the nitroreductase (NTR) system of inducible targeted cell ablation facilitates: 1) large-scale genetic and chemical screens for identifying factors that regulate regeneration and, 2) in vivo time-lapse imaging experiments aimed at investigating regenerative processes more directly. Combining powerful screening and imaging technologies with targeted ablation systems can expand our understanding of how individual stem cell niches are regulated. The former approach promotes the development of therapies aimed at enhancing regenerative potentials in humans, the latter facilitates investigation of phenomena that are otherwise difficult to resolve, such as the role of cellular transdifferentiation or the innate immune system in regenerative paradigms.

show abstract

“…They showed that among various HRE constructs and promoter elements, 5HRE/CMVmp had optimal activation at a low oxygen tension, which is true in the gastrointestinal tract. Harvey et al 21 developed an adenovirus vector for hypoxia-targeted gene therapy using the herpes simplex virus thymidine kinase and bacterial nitroreductase prodrug-activating genes. They showed that 5HRE derived from vascular endothelial growth factor and linked to the CMV minimal promoter could induce optimum luciferase reporter gene expression.…”

Section: Discussionmentioning

confidence: 99%

Lentivirus-mediated RASSF1A expression suppresses aggressive phenotypes of gastric cancer cells in vitro and in vivo

Zhou

et al. 2015

Gene Ther

View full text Add to dashboard Cite

Loss of Ras association domain family protein 1 isoform A (RASSF1A) expression is associated with the development of a variety of human cancers and the expression of carcinoembryonic antigen (CEA) frequently occurs in gastric cancer. This study investigated the effects of RASSF1A expression restoration using a hypoxia-inducible CEA promoter-driven vector on xenograft tumor growth in nude mice and on the in-vitro regulation of gastric cancer cell viability, cell cycle distribution, apoptosis, colony formation and invasion capacity. The data showed that the level of CEA mRNA and protein was much higher in gastric cancer SGC7901 cells than in a second gastric cancer cell line, MKN28, or in the MCF-10A normal epithelial breast cell line. RASSF1A expression was restored in SGC7901 cells compared with the negative control virus-infected SGC7910 cells. RASSF1A expression restoration significantly inhibited gastric cancer cell viability, colony formation and invasion capacity, but induced cell cycle arrest and apoptosis in vitro, especially under hypoxic culture conditions. At the gene level, restoration of RASSF1A expression under hypoxic culture conditions significantly suppressed matrix metalloproteinase-2 expression and prevented cyclinD1 expression. A nude mouse xenograft assay showed that the restoration of RASSF1A expression reduced gastric cancer xenograft formation and growth. In conclusion, the restoration of RASSF1A expression using a hypoxia-inducible and CEA promoter-driven vector suppressed aggressive phenotypes of gastric cancer cells in vitro and in vivo. These results suggest that LV-5HRE-CEAp-RASSF1A gene therapy may be a promising novel approach to treat advanced gastric cancer.

show abstract

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

Cited by 20 publications

References 36 publications

Targeted CDX2 expression inhibits aggressive phenotypes of colon cancer cells in vitro and in vivo

Targeted CDX2 expression inhibits aggressive phenotypes of colon cancer cells in vitro and in vivo

The nitroreductase system of inducible targeted ablation facilitates cell-specific regenerative studies in zebrafish

Lentivirus-mediated RASSF1A expression suppresses aggressive phenotypes of gastric cancer cells in vitro and in vivo

Contact Info

Product

Resources

About