The potential of acetaminophen as a prodrug in gene-directed enzyme prodrug therapy

Thatcher, Natalie J; Edwards, Robert J.; Lemoine, Nicholas R.; Doehmer, Johannes; Davies, Donald S.

doi:10.1038/sj.cgt.7700165

Cited by 14 publications

(7 citation statements)

References 12 publications

(15 reference statements)

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“…The concentrations of paracetamol used to achieve cell kill are similar to those used by Thatcher et al (2000) for prodrug activation using CYP1A2. This group showed decreased cell viability following exposure of fibroblasts overexpressing CYP1A2 to paracetamol.…”

Section: Discussionmentioning

confidence: 98%

Use of horseradish peroxidase for gene-directed enzyme prodrug therapy with paracetamol

2004

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Gene therapy is a potential method of treating cancer with a greater degree of targeting than conventional therapies. In addition, therapy can be directed towards cells within the tumour population that are traditionally resistant to current treatment schedules. Horseradish peroxidase (HRP) can oxidise paracetamol to N-acetyl-p-benzoquinoneimine via a one-electron pathway. Incubation of human cells expressing HRP with 0.5 -10 mM paracetamol reduced clonogenic survival, but had little effect on control cells. A small increase in apoptosis was seen and a decrease in the number of cells undergoing mitosis, consistent with reports in hepatocytes using higher paracetamol concentrations. The cytotoxicity was also seen under conditions of severe hypoxia (catalyst induced anoxia), indicating that the HRP/paracetamol combination may be suitable for hypoxia-targeted gene therapy.

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Section: Discussionmentioning

confidence: 98%

Use of horseradish peroxidase for gene-directed enzyme prodrug therapy with paracetamol

2004

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“…We performed curve fitting of each set of concentration response data and calculations of the lowest effective concentration that produced maximal response (EC max ), the effective concentration that produced 50% of maximal response (EC 50 ), and the highest effective concentration that produced no measurable response (EC min ) values of each of the estrogenic compounds as described previously (Zhu et al 2008b). In some instances, we assessed effects on cell viability by trypan blue exclusion, as described previously (Thatcher et al 2000). …”

Section: Methodsmentioning

confidence: 99%

Increased Expression of Histone Proteins during Estrogen-Mediated Cell Proliferation

Zhu

Edwards²,

Boobis³

2009

Environ Health Perspect

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BackgroundThere is concern about the potential risk posed by compounds with estrogen-like activity present in the environment. As previous studies have shown that combined exposure to such compounds results in dose additivity, it should be possible to assess estrogen exposure with suitable biomarkers of effect.ObjectivesOur goal was to identify candidate protein biomarkers of effect for estrogenic compounds.MethodsIn the search for biomarkers, we assessed the effect of several estrogenic compounds on the expression profile of proteins in breast-derived cell lines varying in their estrogen receptor (ER) phenotype using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. We identified responsive proteins, after separating them by SDS-polyacrylamide gel electrophoresis, and analyzing the trypsin-digested proteins by tandem mass spectrometry.ResultsThe estrogenic compounds 17β-estradiol, genistein, bisphenol A, and endosulfan produced similar protein profile changes in MCF-7 cells (phenotype: ERα+/ERβ+), but had no effect on MDA-MB-231 (ERα−/ERβ+), MCF-10F (ERα−/ERβ+), or MCF-10A (ERα−/ERβ−) cells. The most responsive proteins in MCF-7 cells were identified as histones H2A, H2B, H3, and H4. Histone levels were not increased in cell lines that showed no proliferative response to estrogens despite their rapid intrinsic growth rate in culture.ConclusionOur results indicate that ER-mediated cell proliferation results in up-regulation of core histone proteins.

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“…Transfection of H1A2 MZ cells with human CYP1A2 sensitized them to treatment with acetaminophen, with the generation of a substantial bystander effect (complete killing of V79 cells in a mixture containing 5% transduced H1A2 MZ cells) [95]. Similar bystander effects were seen with transduced SK-OV-3 human ovarian tumor cells and HCT116 human colon tumor cells, but not with MDA-MB-361 breast tumor cells.…”

Section: Prodrugs For Cyp Enzymesmentioning

confidence: 99%

Prodrugs for Gene‐Directed Enzyme‐Prodrug Therapy (Suicide Gene Therapy)

Denny

2003

BioMed Research International

105

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This review focuses on the prodrugs used in suicide gene therapy. These prodrugs need to satisfy a number of criteria. They must be efficient and selective substrates for the activating enzyme, and be metabolized to potent cytotoxins preferably able to kill cells at all stages of the cell cycle. Both prodrugs and their activated species should have good distributive properties, so that the resulting bystander effects can maximize the effectiveness of the therapy, since gene transduction efficiencies are generally low. A total of 42 prodrugs explored for use in suicide gene therapy with 12 different enzymes are discussed, particularly in terms of their physiocochemical properties. An important parameter in determining bystander effects generated by passive diffusion is the lipophilicity of the activated form, a property conveniently compared by diffusion coefficients (log P for nonionizable compounds and log D7 for compounds containing an ionizable centre). Many of the early antimetabolite-based prodrugs provide very polar activated forms that have limited abilities to diffuse across cell membranes, and rely on gap junctions between cells for their bystander effects. Several later studies have shown that more lipophilic, neutral compounds have superior diffusion-based bystander effects. Prodrugs of DNA alkylating agents, that are less cell cycle-specific than antimetabolites and more effective against noncycling tumor cells, appear in general to be more active prodrugs, requiring less prolonged dosing schedules to be effective. It is expected that continued studies to optimize the bystander effects and other properties of prodrugs and the activated species they generate will contribute to improvements in the effectiveness of suicide gene therapy.

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The potential of acetaminophen as a prodrug in gene-directed enzyme prodrug therapy

Cited by 14 publications

References 12 publications

Use of horseradish peroxidase for gene-directed enzyme prodrug therapy with paracetamol

Use of horseradish peroxidase for gene-directed enzyme prodrug therapy with paracetamol

Increased Expression of Histone Proteins during Estrogen-Mediated Cell Proliferation

Prodrugs for Gene‐Directed Enzyme‐Prodrug Therapy (Suicide Gene Therapy)

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