Preclinical evaluation of the pharmacodynamic properties of 2,5-diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone.

2.50
Hdl Handle:
http://hdl.handle.net/10541/76830
Title:
Preclinical evaluation of the pharmacodynamic properties of 2,5-diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone.
Authors:
Ward, Timothy H; Danson, Sarah; McGown, Alan T; Ranson, Malcolm R; Coe, Nic A; Jayson, Gordon C ( 0000-0002-8515-8944 ) ; Cummings, Jeffrey; Hargreaves, Robert H J; Butler, John
Abstract:
PURPOSE: The purpose of our study was to investigate the cellular accumulation, DNA cross-linking ability, and cellular toxicity of RH1 (2,5-diaziridinyl-3-[hydroxymethyl[-6-methyl-1,4-benzoquinone), a novel DNA alkylating agent currently in clinical trials. In addition, the in vivo efficacy of RH1 formulated in different vehicles was also compared. EXPERIMENTAL DESIGN: RH1 is activated by the two-electron reducing enzyme NQO1 [NADPH:quinone oxidoreductase] forming a potent cytotoxic agent that cross-links DNA. We have used whole blood, cell lines, and primary explanted tumor cultures to measure both the cellular accumulation, DNA cross-linking, and cytotoxicity of RH1. Furthermore, the pharmacokinetic and pharmacodynamic characteristics of RH1 formulated in different vehicles were measured in vivo using the validated comet-X assay in mice bearing human tumor xenografts. RESULTS: Accumulation of RH1 was shown to be both time and concentration dependent, reaching a maximum after 2 hours and correlated well with DNA cross-linking measurements. DNA cross-linking in vitro could be detected at low (1-10 nmol/L) concentrations after as little as 2 hours exposure. In primary tumor cultures, RH1 induces much higher levels of DNA cross-links at lower doses than either mitomycin C or cisplatin. In vivo efficacy testing using polyvinyl pyrrolidone, saline, or cyclodextrin as vehicles showed DNA cross-links readily detectable in all tissues examined and was enhanced when given in cyclodextrin compared with polyvinyl pyrrolidone or saline. CONCLUSIONS: RH1 represents a potent bioreductive anticancer drug, which may prove effective in the treatment of cancers, particularly those that overexpress NQO1. DNA cross-linking can be reliably measured in tissue using the validated comet-X assay.
Affiliation:
Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Christie Hospital, Manchester, UK. tward@picr.man.ac.uk
Citation:
Preclinical evaluation of the pharmacodynamic properties of 2,5-diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone. 2005, 11 (7):2695-701 Clin. Cancer Res.
Journal:
Clinical Cancer Research
Issue Date:
1-Apr-2005
URI:
http://hdl.handle.net/10541/76830
DOI:
10.1158/1078-0432.CCR-04-1751
PubMed ID:
15814651
Type:
Article
Language:
en
ISSN:
1078-0432
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorWard, Timothy H-
dc.contributor.authorDanson, Sarah-
dc.contributor.authorMcGown, Alan T-
dc.contributor.authorRanson, Malcolm R-
dc.contributor.authorCoe, Nic A-
dc.contributor.authorJayson, Gordon C-
dc.contributor.authorCummings, Jeffrey-
dc.contributor.authorHargreaves, Robert H J-
dc.contributor.authorButler, John-
dc.date.accessioned2009-08-10T17:15:30Z-
dc.date.available2009-08-10T17:15:30Z-
dc.date.issued2005-04-01-
dc.identifier.citationPreclinical evaluation of the pharmacodynamic properties of 2,5-diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone. 2005, 11 (7):2695-701 Clin. Cancer Res.en
dc.identifier.issn1078-0432-
dc.identifier.pmid15814651-
dc.identifier.doi10.1158/1078-0432.CCR-04-1751-
dc.identifier.urihttp://hdl.handle.net/10541/76830-
dc.description.abstractPURPOSE: The purpose of our study was to investigate the cellular accumulation, DNA cross-linking ability, and cellular toxicity of RH1 (2,5-diaziridinyl-3-[hydroxymethyl[-6-methyl-1,4-benzoquinone), a novel DNA alkylating agent currently in clinical trials. In addition, the in vivo efficacy of RH1 formulated in different vehicles was also compared. EXPERIMENTAL DESIGN: RH1 is activated by the two-electron reducing enzyme NQO1 [NADPH:quinone oxidoreductase] forming a potent cytotoxic agent that cross-links DNA. We have used whole blood, cell lines, and primary explanted tumor cultures to measure both the cellular accumulation, DNA cross-linking, and cytotoxicity of RH1. Furthermore, the pharmacokinetic and pharmacodynamic characteristics of RH1 formulated in different vehicles were measured in vivo using the validated comet-X assay in mice bearing human tumor xenografts. RESULTS: Accumulation of RH1 was shown to be both time and concentration dependent, reaching a maximum after 2 hours and correlated well with DNA cross-linking measurements. DNA cross-linking in vitro could be detected at low (1-10 nmol/L) concentrations after as little as 2 hours exposure. In primary tumor cultures, RH1 induces much higher levels of DNA cross-links at lower doses than either mitomycin C or cisplatin. In vivo efficacy testing using polyvinyl pyrrolidone, saline, or cyclodextrin as vehicles showed DNA cross-links readily detectable in all tissues examined and was enhanced when given in cyclodextrin compared with polyvinyl pyrrolidone or saline. CONCLUSIONS: RH1 represents a potent bioreductive anticancer drug, which may prove effective in the treatment of cancers, particularly those that overexpress NQO1. DNA cross-linking can be reliably measured in tissue using the validated comet-X assay.en
dc.language.isoenen
dc.subjectCell Line Tumouren
dc.subject.meshAnimals-
dc.subject.meshAziridines-
dc.subject.meshBenzoquinones-
dc.subject.meshCell Line, Tumor-
dc.subject.meshCell Proliferation-
dc.subject.meshComet Assay-
dc.subject.meshCross-Linking Reagents-
dc.subject.meshDNA-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshDrug Evaluation, Preclinical-
dc.subject.meshFemale-
dc.subject.meshHumans-
dc.subject.meshMice-
dc.subject.meshMice, Nude-
dc.subject.meshTreatment Outcome-
dc.subject.meshTritium-
dc.subject.meshXenograft Model Antitumor Assays-
dc.titlePreclinical evaluation of the pharmacodynamic properties of 2,5-diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone.en
dc.typeArticleen
dc.contributor.departmentClinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, Christie Hospital, Manchester, UK. tward@picr.man.ac.uken
dc.identifier.journalClinical Cancer Researchen
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