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

Ward, TH, Danson, S, McGown, AT, Ranson, M, Coe, NA, Jayson, GC, Cummings, J, Hargreaves, RJ and Butler, J 2005, 'Preclinical evaluation of the pharmacodynamic properties of 2,5-diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone' , Clinical Cancer Research, 11 (7) , pp. 2695-2701.

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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 [NAD(P)H: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.

Item Type: Article
Themes: Subjects / Themes > Q Science > Q Science (General)
Subjects / Themes > R Medicine > R Medicine (General)
Health and Wellbeing
Subjects outside of the University Themes
Schools: Schools > School of Environment and Life Sciences
Schools > School of Environment and Life Sciences > Biomedical Research Centre
Journal or Publication Title: Clinical Cancer Research
Publisher: American Association for Cancer Research
Refereed: Yes
ISSN: 10780432
Depositing User: H Kenna
Date Deposited: 08 Aug 2007 09:11
Last Modified: 27 Aug 2021 21:58

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