Suicide gene therapy with an adenovirus expressing the fusion gene CD::UPRT in human glioblastomas: different sensitivities correlate with p53 status

Bourbeau, Denis; Lavoie, Geneviève; Nalbantoglu, Joséphine; Massie, Bernard

doi:10.1002/jgm.611

Cited by 23 publications

(25 citation statements)

References 29 publications

(43 reference statements)

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“…This overcoming of resistance was not dependent on the site of origin of the cancer cells as AdCU plus 5-FC was effective against the colon cancer cells that were both sensitive (A-Col1) and resistant (A-Col2) to 5-FU. As previously reported, [1][2][3]10 the AdCD was much less effective than the AdCU in killing the cells. At an MOI of 100 and 100 mM 5-FC, the surviving fraction was between 30 and 50% whereas at the same concentration with AdCU, the surviving fraction was o20% in all samples.…”

Section: Sensitivity Of Primary Cancer Cells To 5-fusupporting

confidence: 74%

“…The recombinant adenovirus expressing either cytosine deaminase (AdCD) and green fluorescent protein (GFP) or CD with uracil phosphoribosyltransferase (AdCU) and GFP were constructed and used as described in Bourbeau et al 10 Cells were plated out at a density of 100 000 cells in 12-well plates. The next day, the cancer cells were infected with either AdCU or AdCD at a multiplicity of infection (MOI) of 25, 50 and 100.…”

Section: Transduction Of Adenovirusmentioning

confidence: 99%

“…10 As bystander effect is essential for this to be an effective therapy, we tested a range of MOI of AdCU on the primary cancer cells to determine the minimum that would be required for toxicity to 5-FC. As the AdCU coexpresses GFP, transduction efficiency could be measured by flow cytometry and presented as a percentage of cells that expressed GFP.…”

Section: Role Of the Uprt In Overcoming The 5-fu Resistancementioning

confidence: 99%

“…9 The vectors tested in this study use the cytosine deaminase (CD) and the uracil phosphoribosyl transferase (UPRT). These vectors have previously shown high efficacy on glioblastoma cell lines, suggesting a potential for the treatment of cancers of the central nervous systems, 10 and possibly cancers of other origins. Through the actions of CD, an enzyme that is present in prokaryotes and fungi but not in multicellular eukaryotes, 11,12 the benign pro-drug 5-FC is converted to the highly cytotoxic 5-FU.…”

Section: Introductionmentioning

confidence: 99%

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Sensitivity of 5-fluorouracil-resistant cancer cells to adenovirus suicide gene therapy

et al. 2006

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A promising approach for cancer gene therapy is the combination of adenovirus vectors (AdV) with the suicide gene cytosine deaminase and uracil phosphoribosyl transferase (CDHUPRT). While such vectors have been tested in tumor cell lines and xenograft models, it is not clear how these therapeutic vectors would perform in primary human tumors. We, thus, examined the effect of the combination of a recombinant adenovirus expressing the CDHUPRT (AdCU) with 5-fluorocytosine (5-FC) on primary cancer cells isolated from the ascites or pleural fluids of patients with metastatic cancers. In such models, we have found a direct correlation between the patients' response to 5-FU and the response shown by the cancer cells in vitro, confirming the clinical relevance of this methodology. Our findings demonstrated that this combination was able to kill primary tumor cells, including those that had developed resistance to 5-FU. Furthermore, while proliferating cells were more susceptible to 5-FU, the combination was effective in both rapid and slow proliferating samples. Our study demonstrated that this gene therapy approach could provide an effective therapeutic option for cancers and is not affected by acquired 5-FU resistance. Also of importance is the effectiveness of this gene therapy approach on slower proliferating cells that is typical of the majority of cancers in vivo. This suggests a greater likelihood that it will be effective in a clinical setting.

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Section: Sensitivity Of Primary Cancer Cells To 5-fusupporting

confidence: 74%

Section: Transduction Of Adenovirusmentioning

confidence: 99%

Section: Role Of the Uprt In Overcoming The 5-fu Resistancementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sensitivity of 5-fluorouracil-resistant cancer cells to adenovirus suicide gene therapy

et al. 2006

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“…Strategies taking advantage of multiple cell-killing pathways targeted by different prodrugs via delivering more than one 'suicide' gene have often yielded increased efficacy. 49,50 However, from a practical perspective, given the safety concerns associated with various delivery vehicles for gene therapy and transgenes, and the resulting stringent regulatory requirements for translation into the clinic, the use of multiple 'suicide' genes is hardly justified when alternative approaches based on a single gene with high prodrug plasticity, such as the dCK.DM.S74E mutant, are available.…”

Section: Bystander Cell Killing Requires Direct Cell-to-cell Contact mentioning

confidence: 99%

Bystander killing of malignant cells via the delivery of engineered thymidine-active deoxycytidine kinase for suicide gene therapy of cancer

Neschadim

Wang²,

Lavie

et al. 2012

Cancer Gene Ther

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Activity and specificity of chemotherapeutic agents against solid tumors can be augmented via the targeted or localized delivery of 'suicide' genes. Selective activation of specific prodrugs in cells expressing the 'suicide' gene drives their elimination by apoptosis, while also enabling the killing of adjacent bystander cells. Strong bystander effects can compensate for poor 'suicide' gene delivery, and depend on the prodrugs used and mechanisms for the acquisition of activated drug by the bystander population, such as the presence of gap junctional intercellular communications. Although a number of 'suicide' gene therapies for cancer have been developed and characterized, such as herpes simplex virus-derived thymidine kinase (HSVtk)-based activation of ganciclovir, their limited success highlights the need for the development of more robust approaches. Limiting activation kinetics and evolution of chemoresistance are major obstacles. Here we describe 'suicide' gene therapy of cancer based on the lentivirus-mediated delivery of a thymidine-active human deoxycytidine kinase variant. This enzyme possesses substrate plasticity that enables it to activate a multitude of prodrugs, some with distinct mechanisms of action. We evaluated the magnitude and mechanisms of bystander effects induced by different prodrugs, and show that when used in combination, they can synergistically enhance the bystander effect while avoiding off-target toxicity.

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Complete regression of glioblastoma by mesenchymal stem cells mediated prodrug gene therapy simulating clinical therapeutic scenario

Altaner

Altanerová²,

Cihova

et al. 2013

Intl Journal of Cancer

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Suicide gene therapy mediated by mesenchymal stem cells with their ability to engraft into tumors makes these therapeutic stem cells an attractive tool to activate prodrugs directly within the tumor mass. In this study, we evaluated the therapeutic efficacy of human mesenchymal stem cells derived from bone marrow and from adipose tissue, engineered to express the suicide gene cytosine deaminase::uracil phosphoribosyltransferase to treat intracerebral rat C6 glioblastoma in a simulated clinical therapeutic scenario. Intracerebrally grown glioblastoma was treated by resection and subsequently with single or repeated intracerebral inoculations of therapeutic stem cells followed by a continuous intracerebroventricular delivery of 5-fluorocytosine using an osmotic pump. Kaplan-Meier survival curves revealed that surgical resection of the tumor increased the survival time of the resected animals depending on the extent of surgical intervention. However, direct injections of therapeutic stem cells into the brain tissue surrounding the postoperative resection cavity led to a curative outcome in a significant number of treated animals. Moreover, the continuous supply of therapeutic stem cells into the brain with growing glioblastoma by osmotic pumps together with continuous prodrug delivery also proved to be therapeutically efficient. We assume that observed curative therapy of glioblastoma by stem cell-mediated prodrug gene therapy might be caused by the destruction of both tumor cells and the niche where glioblastoma initiating cells reside.

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Suicide gene therapy with an adenovirus expressing the fusion gene CD::UPRT in human glioblastomas: different sensitivities correlate with p53 status

Abstract: Our study has shown that p53 status is important for CD::UPRT/5-FC treatment. Moreover, this study demonstrated that the three-dimensional spheroid model is a more stringent in vitro model for suicide gene therapy evaluation than are monolayer cultures.

Cited by 23 publications

References 29 publications

Sensitivity of 5-fluorouracil-resistant cancer cells to adenovirus suicide gene therapy

Sensitivity of 5-fluorouracil-resistant cancer cells to adenovirus suicide gene therapy

Bystander killing of malignant cells via the delivery of engineered thymidine-active deoxycytidine kinase for suicide gene therapy of cancer

Complete regression of glioblastoma by mesenchymal stem cells mediated prodrug gene therapy simulating clinical therapeutic scenario

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