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    Protection of committed murine haemopoietic progenitors against BCNU toxicity does not predict protection of primitive, multipotent spleen colony-forming cells - implications for chemoprotective gene therapy.

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    Authors
    Chinnasamy, Nachimuthu
    Rafferty, Joseph A
    Lashford, Linda S
    Chinnasamy, Dhanalakshmi
    Margison, Geoffrey P
    Thatcher, Nick
    Dexter, T Michael
    Fairbairn, Leslie J
    Affiliation
    CRC Sections of Genome Damage and Repair, Paterson Institute for Cancer Research, Manchester, UK.
    Issue Date
    1999-11
    
    Metadata
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    Abstract
    The effect of expression of an O6-benzylguanine (O6-beG)-resistant mutant (hATPA/GA) of human O6-alkylguanine-DNA alkyltransferase (ATase) on the in vivo toxicity and clastogenicity of the anti-tumour agent N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) to murine bone marrow has been investigated. When compared with control animals, the bipotent granulocyte-macrophage colony-forming (GM-CFC) progenitor population of the hATPA/GA transduced mice were somewhat more resistant to BCNU (1.4-fold, P = 0.047) and this effect was more significant in the presence of the ATase inactivator O6-beG (3. 5-fold, P = 0.001). The polychromatic erythrocytes were also significantly protected against BCNU-induced clastogenicity both in the presence (P < 0.001) and absence of O6-beG (P < 0.05). The primitive, multipotent spleen colony-forming cells (CFU-S) in these animals also showed moderate (1.6-fold, P = 0.034) protection in the absence of O6-beG but in the presence of the inactivator they remained as sensitive to BCNU toxicity as those in the control animals (P = 0.133). This result contrasts with previous findings demonstrating significant hATPA/GA-mediated, O6-beG-resistant protection against the toxicity and clastogenicity of a number of O6-alkylating agents, including temozolomide, fotemustine and chlorozotocin. The possibility that our strategy for protective gene therapy may be highly agent and cell-type specific is unexpected and has possible implications for clinical trials of this approach using BCNU or related agents.
    Citation
    Protection of committed murine haemopoietic progenitors against BCNU toxicity does not predict protection of primitive, multipotent spleen colony-forming cells - implications for chemoprotective gene therapy. 1999, 13 (11):1776-83 Leukemia
    Journal
    Leukemia
    URI
    http://hdl.handle.net/10541/90155
    PubMed ID
    10557052
    Type
    Article
    Language
    en
    ISSN
    0887-6924
    Collections
    All Paterson Institute for Cancer Research

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