Hypoxia- and radiation-activated Cre/loxP ‘molecular switch’ vectors for gene therapy of cancer

Greco, Olga; Joiner, Michael C.; Doleh, A.; Powell, Angela; Hillman, Gilda G.; Scott, Simon D.

doi:10.1038/sj.gt.3302640

Cited by 33 publications

(21 citation statements)

References 20 publications

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“…Many studies, including human clinical trials using HSVtkexpressing Adv, have confirmed the efficacy of this gene therapy approach when delivered through intratumoral injection. 15,[25][26][27][28] However, few studies have evaluated the usefulness of this system to treat metastases through Therapeutic effect of PEGylated adenovirus vector X Yao et al intravenous injection. We showed that PEG-Ad-TERT/ HSVtk induced strong antitumor effects against metastases without side effects, although PEG-Ad-CMV/ HSVtk did induce significant side effects in spite of strong antitumor effects (Figures 4 and 5).…”

Section: Discussionmentioning

confidence: 99%

Systemic administration of a PEGylated adenovirus vector with a cancer-specific promoter is effective in a mouse model of metastasis

et al. 2009

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Cancer gene therapy by adenovirus vectors (Advs) for metastatic cancer is limited because systemic administration of Adv produces low therapeutic effect and severe side effects. In this study, we generated a dual cancer-specific targeting vector system by using PEGylation and the telomere reverse transcriptase (TERT) promoter and attempted to treat experimental metastases through systemic administration of the vectors. We first optimized the molecular size of PEG and modification ratios used to create PEG-Ads. Systemic administration of PEG-Ad with 20-kDa PEG at a 45% modification ratio (PEG[20K/45%]-Ad) resulted in higher tumor-selective transgene expression than unmodified Adv. Next, we examined the effectiveness against metastases and side effects of a TERT promoterdriven PEG[20K/45%]-Ad containing the herpes simplex virus thymidine kinase (HSVtk) gene (PEG-Ad-TERT/ HSVtk). Systemic administration of PEG-Ad-TERT/HSVtk showed superior antitumor effects against metastases with negligible side effects. A cytomegalovirus (CMV) promoter-driven PEG[20K/45%]-Ad also produced antimetastatic effects, but these were accompanied by side effects. Combining PEG-Ad-TERT/HSVtk with etoposide or 5-fluorouracil enhanced the therapeutic effects with negligible side effects. These results suggest that modification with 20-kDa PEG at a 45% modification ratio is the optimal condition for PEGylation of Adv, and PEG-Ad-TERT/HSVtk is a prototype Adv for systemic cancer gene therapy against metastases.

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Section: Discussionmentioning

confidence: 99%

Systemic administration of a PEGylated adenovirus vector with a cancer-specific promoter is effective in a mouse model of metastasis

et al. 2009

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“…Several vectors have been used to drive expression of HSV-tk for killing of tumor cells. The effectiveness of suicidal gene therapy mediated by HRE cre/lox driving HSV-tk has been evaluated in a model of tumor xenografts implanted in nude mice (Greco et al, 2006). In a similar strategy a hypoxia regulated expression vector was used to drive the expression of cytosine deaminase gene which activates another pro-drug 5-fluorocytosine to form the highly toxic 5-fluoruracil ).…”

Section: Use Of Cytotoxic or Suicidal Approachmentioning

confidence: 99%

Hypoxia Responsive Vectors Targeting Astrocytes in Glioma

Biswal¹,

Prentice²,

Blanks³

2012

Novel Therapeutic Concepts in Targeting Glioma

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“…The single vector switch was also tested in nude mouse xenograft models, in which it induced significant growth delay and tumor eradication. 134 …”

Section: Inducible Promoter Systemsmentioning

confidence: 99%

Targeted gene therapy in radiotherapy

Kamenšek¹,

Serša²

2008

Radiology and Oncology

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out of the primary tumor are not destroyed. In addition, there are some radio-resistant cells within a single tumor mass that may survive despite a relatively high radiation dose. The efficacy of radiotherapy is also limited by chronic and intermittent hypoxia in the tumors.To increase the efficacy of radiotherapy, while minimizing its side effects, developments have been made in combining radiotherapy with chemotherapy and, lately, gene therapy. Gene therapy and its combination with radiotherapyGene therapy consists of the transfer of exogenous genes, called transgenes, into human somatic cells and the expression of these genes in transfected cells for a therapeutic purpose. In cancer treatment, this means either correction of genetic defects, characteristic of cancer cells, or induction of targeted tumor cell death. 3 In gene correction or replacement approach, a defective or inactivated tumor suppressor gene is replaced, for example to increase radiation-induced apoptosis (wild-type p53 replacement therapy) or high oncogene expression levels are repressed with the use of antisense, ribozymes or siRNA technology. However, because cancer is a consequence of countless genetic mutations, most anti-tumor therapies aim to destroy cancer cells, rather than correct these complex defects. Strategies to destroy cancer cells can be exerted in different ways; by gene directed chemotherapy, potentiation of immune response and targeting of the tumor vasculature (Table 1). Recent advances in gene therapy approaches have allowed researchers to successfully combine gene therapy with radiotherapy. 4,5 There are many potential benefits of combining radiotherapy with gene therapy:• Gene therapy and radiotherapy techniques have different mechanisms of action and they target best at different parts of the cell cycle, which may result in an additive effect ( Figure 1).• Gene therapy can cause radiosensitization, which means that a synergistic (supra-additive) anti-tumor effect is possible ( Figure 1).• Radiation can enhance the "bystander effect" of gene therapy, meaning that more Gene therapy strategy GenesGenetic replacement or correction therapy p53, CTS1, MDA7, Suicide gene therapy (gene chemotherapy) Endogenous precursors HSV-tk, CD, CD/HSV-tk fusion, HRP, IAA Exogenous precursors iNOS Gene based immunotherapy TNF-α, IFN-γ, IL-12…, tumor associated antigens (PSA)Vascular-targeted gene therapy VEGF-antisense, soluble endostatin, angiostatin, vazostatin, CTS1, Chimeric Tumor Suppressor 1 (synthetic variant of wild-type p53); HSV-tk, Herpes Simplex Virus thymidine kinase; CD, Cytosine Deaminase; HRP, Horseradish Peroxidase; IAA, Indol-3-Acetic Acid; iNOS, inducible Nitric Oxide Synthase; TNF-α, Tumor Necrosis Factor-α; IL-12, Interleukin-12; PSA, Prostate Specific Antigen; VEGF, Vascular Endothelial Growth Factor. Radiol Oncol 2008; 42(3): . Unauthenticated Download Date | 5/9/18 6:42 PM cells are affected by gene therapy than are transfected initially. This is probably because of the release of products of therapeutic g...

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Hypoxia- and radiation-activated Cre/loxP ‘molecular switch’ vectors for gene therapy of cancer

Cited by 33 publications

References 20 publications

Systemic administration of a PEGylated adenovirus vector with a cancer-specific promoter is effective in a mouse model of metastasis

Systemic administration of a PEGylated adenovirus vector with a cancer-specific promoter is effective in a mouse model of metastasis

Hypoxia Responsive Vectors Targeting Astrocytes in Glioma

Targeted gene therapy in radiotherapy

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