• 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

    Reciprocal relationship between O6-methylguanine-DNA methyltransferase P140K expression level and chemoprotection of hematopoietic stem cells.

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Authors
    Milsom, Michael D
    Jerabek-Willemsen, Moran
    Harris, Chad E
    Schambach, Axel
    Broun, Emily
    Bailey, J
    Jansen, Michael
    Schleimer, David
    Nattamai, Kalpana
    Wilhelm, Jamie
    Watson, Amanda J
    Geiger, Hartmut
    Margison, Geoffrey P
    Moritz, Thomas
    Baum, Christopher
    Thomale, Jürgen
    Williams, David A
    Show allShow less
    Affiliation
    Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
    Issue Date
    2008-08-01
    
    Metadata
    Show full item record
    Abstract
    Retroviral-mediated delivery of the P140K mutant O(6)-methylguanine-DNA methyltransferase (MGMT(P140K)) into hematopoietic stem cells (HSC) has been proposed as a means to protect against dose-limiting myelosuppressive toxicity ensuing from chemotherapy combining O(6)-alkylating agents (e.g., temozolomide) with pseudosubstrate inhibitors (such as O(6)-benzylguanine) of endogenous MGMT. Because detoxification of O(6)-alkylguanine adducts by MGMT is stoichiometric, it has been suggested that higher levels of MGMT will afford better protection to gene-modified HSC. However, accomplishing this goal would potentially be in conflict with current efforts in the gene therapy field, which aim to incorporate weaker enhancer elements to avoid insertional mutagenesis. Using a panel of self-inactivating gamma-retroviral vectors that express a range of MGMT(P140K) activity, we show that MGMT(P140K) expression by weaker cellular promoter/enhancers is sufficient for in vivo protection/selection following treatment with O(6)-benzylguanine/temozolomide. Conversely, the highest level of MGMT(P140K) activity did not promote efficient in vivo protection despite mediating detoxification of O(6)-alkylguanine adducts. Moreover, very high expression of MGMT(P140K) was associated with a competitive repopulation defect in HSC. Mechanistically, we show a defect in cellular proliferation associated with elevated expression of MGMT(P140K), but not wild-type MGMT. This proliferation defect correlated with increased localization of MGMT(P140K) to the nucleus/chromatin. These data show that very high expression of MGMT(P140K) has a deleterious effect on cellular proliferation, engraftment, and chemoprotection. These studies have direct translational relevance to ongoing clinical gene therapy studies using MGMT(P140K), whereas the novel mechanistic findings are relevant to the basic understanding of DNA repair by MGMT.
    Citation
    Reciprocal relationship between O6-methylguanine-DNA methyltransferase P140K expression level and chemoprotection of hematopoietic stem cells. 2008, 68 (15):6171-80 Cancer Res.
    Journal
    Cancer Research
    URI
    http://hdl.handle.net/10541/68737
    DOI
    10.1158/0008-5472.CAN-08-0320
    PubMed ID
    18676840
    Type
    Article
    Language
    en
    ISSN
    1538-7445
    ae974a485f413a2113503eed53cd6c53
    10.1158/0008-5472.CAN-08-0320
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research
    Carcinogenesis Group

    entitlement

    Related articles

    • Characterisation of a P140K mutant O6-methylguanine-DNA-methyltransferase (MGMT)-expressing transgenic mouse line with drug-selectable bone marrow.
    • Authors: Kramer BA, Lemckert FA, Alexander IE, Gunning PW, McCowage GB
    • Issue date: 2006 Sep
    • Direct reversal of DNA damage by mutant methyltransferase protein protects mice against dose-intensified chemotherapy and leads to in vivo selection of hematopoietic stem cells.
    • Authors: Ragg S, Xu-Welliver M, Bailey J, D'Souza M, Cooper R, Chandra S, Seshadri R, Pegg AE, Williams DA
    • Issue date: 2000 Sep 15
    • Hematoprotection and enrichment of transduced cells in vivo after gene transfer of MGMT(P140K) into hematopoietic stem cells.
    • Authors: Jansen M, Sorg UR, Ragg S, Flasshove M, Seeber S, Williams DA, Moritz T
    • Issue date: 2002 Sep
    • Vector design for expression of O6-methylguanine-DNA methyltransferase in hematopoietic cells.
    • Authors: Schambach A, Baum C
    • Issue date: 2007 Aug 1
    • Differential competitive resistance to methylating versus chloroethylating agents among five O6-alkylguanine DNA alkyltransferases in human hematopoietic cells.
    • Authors: Fontes AM, Davis BM, Encell LP, Lingas K, Covas DT, Zago MA, Loeb LA, Pegg AE, Gerson SL
    • Issue date: 2006 Jan
    DSpace software (copyright © 2002 - 2023)  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.