• Login
    View Item 
    •   Home
    • The Manchester Institute Cancer Research UK
    • All Paterson Institute for Cancer Research
    • View Item
    •   Home
    • The Manchester Institute Cancer Research UK
    • All Paterson Institute for Cancer Research
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of ChristieCommunitiesTitleAuthorsIssue DateSubmit DateSubjectsThis CollectionTitleAuthorsIssue DateSubmit DateSubjects

    My Account

    LoginRegister

    Local Links

    The Christie WebsiteChristie Library and Knowledge Service

    Statistics

    Display statistics

    Studies on the molecular pharmacology of GR63178A. A novel pentacyclic pyrolloquinone anticancer drug.

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Authors
    Cummings, J
    Graham, M A
    Hoey, Brigid M
    Butler, John
    Fry, A M
    Hickson, I D
    Leonard, G
    French, R
    Smyth, J F
    Affiliation
    Imperial Cancer Research Fund, Western General Hospital, Edinburgh, U.K.
    Issue Date
    1992-08-04
    
    Metadata
    Show full item record
    Abstract
    GR63178A (NSC D611615) is the second pentacyclic pyrolloquinone to be evaluated clinically as an anticancer drug. Its mechanism of action is unknown but may be related either to its quinone group or planar ring system. In this report we have investigated the ability of GR63178A to bind non-covalently to DNA, inhibit topoisomerase II and undergo reduction to reactive free radical species. Using two DNA duplexes, a 12-mer oligonucleotide which is a preferred sequence for minor groove binders and a hexamer which is a preferred sequence for intercalators, no evidence of significant binding with GR63178A was found. Neither GR63178A nor GR54374X (its 9-hydroxy metabolite) inhibited purified human topoisomerase II in a decatenation assay. Free radical chemistry was studied by both pulse radiolysis and ESR spectroscopy as well as by in vitro drug incubations with NADPH-fortified rat liver microsomes and purified cytochrome P450 reductase. The one-electron reduction potential of GR63178A was -207 mV +/- 10 which is much more positive than other quinone-containing anticancer drugs such as doxorubicin, mitomycin C and mitozantrone. GR63178A underwent enzyme-catalysed quinone reduction more readily than doxorubicin but produced significantly fewer reactive oxygen species. No evidence was detected of drug-induced, radical-mediated DNA damage in vitro using pBR322 plasmid DNA. Disproportionation of the GR63178A semi-quinone free radical proceeded with a rate constant of 1 x 10(9) M-1 sec-1 under anaerobic conditions, one order of magnitude faster than doxorubicin. The preferential disproportionation of the semi-quinone may explain our inability to detect a free radical signal by ESR. The hydroquinone of GR63178A was stable and exhibited strong visible absorption with a bathochromic shift of 120 nm over the parent drug. These unusual properties may be due to the hydroquinone undergoing a form of keto-enol tautomerization. Thus, GR63178A free radical formation does not appear to result in significant drug activation. In conclusion, GR63178A is unlikely to mediate its antitumour activity by DNA binding, topoisomerase II inhibition or free radical formation in direct contrast to similar anthracycline- and anthraquinone-based anticancer drugs.
    Citation
    Studies on the molecular pharmacology of GR63178A. A novel pentacyclic pyrolloquinone anticancer drug. 1992, 44 (3):433-9 Biochem. Pharmacol.
    Journal
    Biochemical Pharmacology
    URI
    http://hdl.handle.net/10541/108908
    DOI
    10.1016/0006-2952(92)90433-J
    PubMed ID
    1324674
    Type
    Article
    Language
    en
    ISSN
    0006-2952
    ae974a485f413a2113503eed53cd6c53
    10.1016/0006-2952(92)90433-J
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

    entitlement

    Related articles

    • The effect of the anthrapyrazole antitumour agent CI941 on rat liver microsome and cytochrome P-450 reductase mediated free radical processes. Inhibition of doxorubicin activation in vitro.
    • Authors: Graham MA, Newell DR, Butler J, Hoey B, Patterson LH
    • Issue date: 1987 Oct 15
    • The comparative disposition of the pyrolloquinone GR63178A and its 9-hydroxy metabolite GR54374X in sensitive and resistant mouse colon adenocarcinoma.
    • Authors: French RC, Cummings J, MacLellan A, MacPherson JS, Ritchie AA, Smyth JF
    • Issue date: 1993
    • Chromatographic characterisation of six human metabolites of the new anticancer drug GR63178A.
    • Authors: Cummings J, French RC, MacLellan A, Smyth JF
    • Issue date: 1991
    • Interactions of anticancer quinone drugs, aclacinomycin A, adriamycin, carbazilquinone, and mitomycin C, with NADPH-cytochrome P-450 reductase, xanthine oxidase and oxygen.
    • Authors: Komiyama T, Kikuchi T, Sugiura Y
    • Issue date: 1986 Aug
    • Bioreduction of idarubicin and formation of ROS responsible for DNA cleavage by NADPH-cytochrome P450 reductase and its potential role in the antitumor effect.
    • Authors: Celik H, Arinç E
    • Issue date: 2008
    DSpace software (copyright © 2002 - 2019)  DuraSpace
    Quick Guide | Contact Us
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.