Reduced growth in response to ganciclovir treatment of subcutaneous xenografts expressing HSV-tk in the vascular compartment

Mavria, Georgia; Cd, Porter

doi:10.1038/sj.gt.3301483

Cited by 16 publications

(29 citation statements)

References 27 publications

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“…Three previous studies reported the effectiveness of TK targeting in tumor endothelium as antitumoral strategy. [50][51][52] In two cases, 50,51 TK was also expressed in tumor cells as nonspecific promoters were used. In the experimental model established by Mavria and Porter, 52 the ecotropic retrovirus expressing TK could only infect the vasculature and not the human tumor cells.…”

Section: Discussionmentioning

confidence: 99%

“…[50][51][52] In two cases, 50,51 TK was also expressed in tumor cells as nonspecific promoters were used. In the experimental model established by Mavria and Porter, 52 the ecotropic retrovirus expressing TK could only infect the vasculature and not the human tumor cells. This latter study illustrates the relevance of vascular TK expression in tumor growth reduction, compared to tumor cell transduction alone.…”

Section: Discussionmentioning

confidence: 99%

“…In a preliminary study, the VE-cadherin promoter was able to drive LacZ expression in mouse endothelium, when targeted with adenoviral vectors (T. Moll, I. Dreher and A. Muhs, personal communication), indicating that the promoter is still active using this approach. However, alternative means to target TK in tumor endothelium of adult mice exist: (i) although adenovirus vectors have been extensively used, 12,14,51,68 other gene therapy vectors were shown to efficiently transduce endothelial cells in vivo, such as liposomes 30,69,70 or retroviruses, 50,52 and (ii) promoters showing endothelial-specific transcriptional activity have been described including those for tie-2 71 and flk-1 72 genes. Therefore, several routes should be tested and compared to achieve optimal TK delivery and tumor growth inhibition.…”

Section: Discussionmentioning

confidence: 99%

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Expression of thymidine kinase driven by an endothelial-specific promoter inhibits tumor growth of Lewis lung carcinoma cells in transgenic mice

et al. 2003

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The possibility of inhibiting tumor growth by limiting angiogenesis has raised considerable interest. In this study, we examined the feasibility of inhibiting tumor growth by targeting a suicide gene in the endothelium. Toxicity must be directed solely to angiogenic cells. Therefore, we used the herpes simplex virus-thymidine kinase (TK) gene, in combination with the prodrug ganciclovir (GCV), which affects replicative cells. To test this strategy, we produced transgenic mice carrying the TK gene driven by the vascular endothelial (VE)-cadherin promoter. Lewis lung carcinoma cells were injected subcutaneously to establish tumors and to test the effect of GCV on tumor growth. In two independent transgenic lines, GCV treatment (75 mg/kg/day) resulted in a 66-71% reduction of tumor volume at day 20 postimplantation compared to wild-type mice (650 and 550 versus 1930 mm 3 , Po0.02 and 0.01, respectively), whereas no significant difference was observed when vehicle alone was injected. Tumor growth inhibition was accompanied by a marked reduction in tumor vascular density (151 versus 276 vessels/mm 2 , Po0.05) and an increase in tumor cell death, suggesting that tumor growth inhibition was caused by a reduction in tumor angiogenesis. Our data support the potential utility of endothelial targeting of suicide genes in cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Expression of thymidine kinase driven by an endothelial-specific promoter inhibits tumor growth of Lewis lung carcinoma cells in transgenic mice

et al. 2003

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“…Endothelial cells are normally quiescent but become activated in tumours, 8 rendering them sensitive to infection, and we have demonstrated that herpes simplex virus thymidine kinase (TK) expression in tumour vasculature followed by the administration of the prodrug ganciclovir can significantly reduce the growth of tumour xenografts. 9 Multiple levels of vector specificity can be envisaged, such as the use of modified envelope proteins or the expression of a specific therapeutic product. In this study, we have focused on the introduction of endothelial cell-specific transcriptional control.…”

Section: Introductionmentioning

confidence: 99%

Retroviral hybrid LTR vector strategy: functional analysis of LTR elements and generation of endothelial cell specificity

2004

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Transcriptional targeting is an important aspect of developing gene therapy vectors in order to restrict transgene expression to selected target cells. One approach, when using retroviral vectors, is to replace viral transcriptional control elements within the long terminal repeat (LTR) with sequences imparting the desired specificity. We have developed such hybrid LTR retroviruses, incorporating sequences from each of the human promoters for flt-1, ICAM-2 and KDR, as part of our antivascular cancer gene therapy strategy targeting tumour endothelial cells. The chosen fragments were used to replace the enhancer or combined enhancer and proximal promoter regions of the viral LTR. All showed activity in primary human breast microvascular endothelial cells, with viruses incorporating ICAM-2 sequences exhibiting the greatest specificity versus nonendothelial cells in vitro and a marked alteration of specificity towards endothelial cells in a subcutaneous xenograft model in vivo. Moreover, our study documents the effect of enhancer and/or proximal promoter deletion on LTR activity and reports that differential dependence in different cell lines can give the false impression of specificity if experiments are not adequately controlled. This finding also has implications for other retroviral vector designs seeking to provide transcriptional specificity and for their safety with respect to prevention of gene activation at sites of proviral integration.

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“…17,18 The dependence of tumours on a vascular network for growth and the greater accessibility of vessels compared to tumour cells make this an attractive target for gene therapy. To this end, we are developing vectors for systemic delivery to target tumour vasculature.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional targeting of acute hypoxia in the tumour stroma is a novel and viable strategy for cancer gene therapy

Ingram

Porter

2005

Gene Ther

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Deregulated tumour growth and neovascularization result in an inadequate tumour blood supply, leading to areas of chronic hypoxia and necrosis. Irregular vascular structure and abnormal tumour physiology also cause erratic blood flow in tumour vessels. We reasoned that tumour stroma, including vascular endothelial cells, would consequently experience transient hypoxia that may allow transcriptional targeting as part of an antivascular gene therapy approach to cancer. To exploit hypoxia for transcriptional regulation, retroviral vectors were generated with modified LTRs: a 6-mer of hypoxia response elements in place of the viral enhancer produced near wild-type levels of expression in hypoxia but was functionally inert in normoxia. In a tumour xenograft model, expression was mainly around areas of necrosis, which were shown to be hypoxic; no expression was detected in tumour stroma. Time-course experiments in vitro demonstrated that expression was transient in response to a hypoxic episode, such that a reporter gene would be insensitive to acute hypoxia in vivo. In contrast, a significant therapeutic effect was seen upon ganciclovir administration with a vector expressing thymidine kinase (TK) in the tumour stroma. Expression of TK was more effective when targeted to acute hypoxia in the stroma compared to chronic hypoxia in the poorly vascularized regions of the tumour cell compartment. The data presented here are evidence that hypoxia in the stromal compartment does occur and that transient hypoxia constitutes a valid therapeutic target.

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Reduced growth in response to ganciclovir treatment of subcutaneous xenografts expressing HSV-tk in the vascular compartment

Cited by 16 publications

References 27 publications

Expression of thymidine kinase driven by an endothelial-specific promoter inhibits tumor growth of Lewis lung carcinoma cells in transgenic mice

Expression of thymidine kinase driven by an endothelial-specific promoter inhibits tumor growth of Lewis lung carcinoma cells in transgenic mice

Retroviral hybrid LTR vector strategy: functional analysis of LTR elements and generation of endothelial cell specificity

Transcriptional targeting of acute hypoxia in the tumour stroma is a novel and viable strategy for cancer gene therapy

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