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    Modulation of O6-alkylating agent induced clastogenicity by enhanced DNA repair capacity of bone marrow cells.

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    Authors
    Chinnasamy, Nachimuthu
    Fairbairn, Leslie J
    Laher, J
    Willington, Mark
    Rafferty, Joseph A
    Affiliation
    CRC Section of Haemopoietic Cell, Paterson Institute for Cancer Research, Christine Hospital NHS Trust, Mancester M20 4BX, UK.
    Issue Date
    1998-08-07
    
    Metadata
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    Abstract
    The murine bone marrow micronucleus assay has been used to examine (1) the potentiation of fotemustine and streptozotocin induced-clastogenicity by the O6-alkylguanine-DNA alkyltransferase (ATase) inactivator O6-benzylguanine (O6-beG) and (2) the level of protection afforded against this potentiation by retrovirus-mediated expression of an O6-beG-resistant mutant of human ATase (haTPA/GA) in mouse bone marrow. Both fotemustine and streptozotocin induced significantly higher levels of micronucleated polychromatic erythrocytes (p < 0.001 for the highest doses studied) compared to those seen in vehicle-treated animals. The number of micronuclei produced by either agent was dramatically elevated by pretreatment with O6-beG (p < 0.001). Furthermore, in myeloablated mice reconstituted with bone marrow expressing the O6-beG-resistant hATPA/GA as a result of retroviral gene transfer, the frequency of micronucleus formation following exposure of mice to otherwise clastogenic doses of fotemustine or streptozotocin, in the presence of O6-beG, wash highly significantly reduced (p < 0.001 for both agents) relative to that in mock transduced controls. These data clearly implicate O6-chloroethyl- and O6-methylguanine as clastogenic lesions in vivo and establish ATase as a major protective mechanism operating to reduce the frequency of such damage. The potentiation of drug induced clastogenicity by O6-beG suggests that the clinical use of this inactivator in combination with O6-alkylating agents, could substantially increase the risk of therapy related malignancy. Nevertheless the use of hATPA/GA as a protective mechanism via gene therapy may overcome this risk.
    Citation
    Modulation of O6-alkylating agent induced clastogenicity by enhanced DNA repair capacity of bone marrow cells. 1998, 416 (1-2):1-10 Mutat. Res.
    Journal
    Mutation Research
    URI
    http://hdl.handle.net/10541/92695
    PubMed ID
    9725988
    Type
    Article
    Language
    en
    ISSN
    0027-5107
    Collections
    All Paterson Institute for Cancer Research

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