Concomitant expression of<i>E. coli</i>cytosine deaminase and uracil phosphoribosyltransferase improves the cytotoxicity of 5-fluorocytosine

Tiraby, MichÃ¨le; Cazaux, Christophe; Baron, Michel; Drocourt, Daniel; Reynes, Jean-Paul; Tiraby, GÃ©rard

doi:10.1111/j.1574-6968.1998.tb13205.x

Cited by 67 publications

(18 citation statements)

References 16 publications

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“…Other investigators have used cytosine deaminase (CD) gene transfer, which converts the antifungal drug 5-fluorocytosine (5-FC) into the cytotoxic 5-fluorouracil (5-FU) [40,41] by catalyzing the hydrolytic deamination of cytosine into uracil and by the further conversion of 5-FU into potent anti-metabolites (5-FdUMP, 5-FdUTP, 5-FUTP) by cellular enzymes. These compounds inhibit thymidylate synthase and the production of RNA and DNA, resulting in cell death.…”

Section: Evolution Of Safety Switchesmentioning

confidence: 99%

Improving the safety of T-Cell therapies using an inducible caspase-9 gene

Zhou

Brenner

2016

Experimental Hematology

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Adoptive transfer of T cells can be an effective anti-cancer treatment. However, uncontrolled or unpredictable immediate or persistent toxicities are a source of concern. The ability to conditionally eliminate aberrant cells in vivo therefore is becoming a critical step for the successful translation of this approach to the clinic. We review the evolution of safety systems, focusing on a suicide switch that can be expressed stably and efficiently in human T cells without impairing phenotype, function or antigen specificity. This system is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional dimerization in the presence of an otherwise bioinert small molecule drug. When exposed to the synthetic dimerizing drug, the inducible caspase 9 (iC9) becomes activated and leads to the rapid apoptosis of cells expressing this construct. We have demonstrated the clinical feasibility and efficacy of this approach after haploidentical hematopoietic stem cell transplant (haplo-HSCT). Here we review the benefits and limitations of the approach.

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Section: Evolution Of Safety Switchesmentioning

confidence: 99%

Improving the safety of T-Cell therapies using an inducible caspase-9 gene

Zhou

Brenner

2016

Experimental Hematology

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“…Cytidine deaminase is a pyrimidine salvage enzyme that can be derived from bacteria ( Escherichia coli ) or yeast ( Saccharomyces cerevisiae ) and that converts the prodrug 5-fluorocytosine (5-FC) into the cytotoxic agent 5-FU. In turn, UPRT converts 5-FU into its main toxic metabolite, 5-fluoro-2'-deoxyuridine monophosphate (5-fluoro-dUMP) [186], which inhibits the cellular thymidylate synthase enzyme and subsequently DNA synthesis [187]. Oncolytic poxviruses, herpesviruses, VSV, and adenoviruses expressing one or both of these enzymes have been engineered for combination with 5-FU based chemotherapy.…”

Section: Combination Therapy With Ovs and Drugs: More Than The Summentioning

confidence: 99%

Bugs and Drugs: Oncolytic Virotherapy in Combination with Chemotherapy

Wennier

Liu

McFadden

2012

CPB

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Single agent therapies are rarely successful in treating cancer, particularly at metastatic or end stages, and survival rates with monotherapies alone are generally poor. The combination of multiple therapies to treat cancer has already driven significant improvements in the standard of care treatments for many types of cancers. The first combination treatments exploited for cancer therapy involved the use of several cytotoxic chemotherapy agents. Later, with the development of more targeted agents, the use of novel, less toxic drugs, in combination with the more classic cytotoxic drugs has proven advantageous for certain cancer types. Recently, the combination of oncolytic virotherapy with chemotherapy has shown that the use of these two therapies with very distinct anti-tumor mechanisms may also lead to synergistic interactions that ultimately result in increased therapeutic effects not achievable by either therapy alone. The mechanisms of synergy between oncolytic viruses (OVs) and chemotherapeutic agents are just starting to be elucidated. It is evident, however, that the success of these OV-drug combinations depends greatly on the particular O V, the drug(s) selected, and the cancer type targeted. This review summarizes the different OV-drug combinations investigated to date, including the use of second generation armed OVs, which have been studied with the specific purpose of generating synergistic interactions with particular chemotherapy agents. The known mechanisms of synergy between these OV-drug combinations are also summarized. The importance of further investigating these mechanisms of synergy will be critical in order to maximize the therapeutic efficacy of OV-drug combination therapies in the future.

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“…Heterologous expression of E. coli codA was shown to confer 5-FC sensitivity to mammalian cells, ordinarily not producing CD (18). Concomitant expression of E. coli CD and UPRT as a fusion protein, encoded by codA :: upp , was shown to further enhance the 5-FC cytotoxicity (19). A recent study on pyrimidine salvage in Streptomyces species indicated a lack of CD activity but sensitivity towards 5-FU (20).…”

Section: Introductionmentioning

confidence: 99%

A novel method to generate unmarked gene deletions in the intracellular pathogen Rhodococcus equi using 5-fluorocytosine conditional lethality

Geize

Jong

Hessels

et al. 2008

Nucleic Acids Research

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A novel method to efficiently generate unmarked in-frame gene deletions in Rhodococcus equi was developed, exploiting the cytotoxic effect of 5-fluorocytosine (5-FC) by the action of cytosine deaminase (CD) and uracil phosphoribosyltransferase (UPRT) enzymes. The opportunistic, intracellular pathogen R. equi is resistant to high concentrations of 5-FC. Introduction of Escherichia coli genes encoding CD and UPRT conferred conditional lethality to R. equi cells incubated with 5-FC. To exemplify the use of the codA::upp cassette as counter-selectable marker, an unmarked in-frame gene deletion mutant of R. equi was constructed. The supA and supB genes, part of a putative cholesterol catabolic gene cluster, were efficiently deleted from the R. equi wild-type genome. Phenotypic analysis of the generated ΔsupAB mutant confirmed that supAB are essential for growth of R. equi on cholesterol. Macrophage survival assays revealed that the ΔsupAB mutant is able to survive and proliferate in macrophages comparable to wild type. Thus, cholesterol metabolism does not appear to be essential for macrophage survival of R. equi. The CD-UPRT based 5-FC counter-selection may become a useful asset in the generation of unmarked in-frame gene deletions in other actinobacteria as well, as actinobacteria generally appear to be 5-FC resistant and 5-FU sensitive.

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Concomitant expression ofE. colicytosine deaminase and uracil phosphoribosyltransferase improves the cytotoxicity of 5-fluorocytosine

Cited by 67 publications

References 16 publications

Improving the safety of T-Cell therapies using an inducible caspase-9 gene

Improving the safety of T-Cell therapies using an inducible caspase-9 gene

Bugs and Drugs: Oncolytic Virotherapy in Combination with Chemotherapy

A novel method to generate unmarked gene deletions in the intracellular pathogen Rhodococcus equi using 5-fluorocytosine conditional lethality

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