TH Ward
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; Butler, J
Authors
S Danson
AT McGown
M Ranson
NA Coe
GC Jayson
J Cummings
RJ Hargreaves
J Butler
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 [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.
Citation
Ward, T., Danson, S., McGown, A., Ranson, M., Coe, N., Jayson, G., …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), 2695-2701. https://doi.org/10.1158/1078-0432.CCR-04-1751
Journal Article Type | Article |
---|---|
Publication Date | Apr 1, 2005 |
Deposit Date | Aug 8, 2007 |
Journal | Clinical Cancer Research |
Print ISSN | 1078-0432 |
Publisher | American Association for Cancer Research |
Peer Reviewed | Peer Reviewed |
Volume | 11 |
Issue | 7 |
Pages | 2695-2701 |
DOI | https://doi.org/10.1158/1078-0432.CCR-04-1751 |
Publisher URL | http://dx.doi.org/10.1158/1078-0432.CCR-04-1751 |
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