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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.
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
html.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.


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