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    O(6)-(4-bromothenyl)guanine improves the therapeutic index of temozolomide against A375M melanoma xenografts.

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    Authors
    Middleton, Mark R
    Kelly, Jane
    Thatcher, Nick
    Donnelly, Dorothy J
    McElhinney, R S
    McMurry, T B
    McCormick, J E
    Margison, Geoffrey P
    Affiliation
    Cancer Research Campaign Department of Carcinogenesis, Paterson Institute for Cancer Research, Manchester, UK. mmiddleton@picr.man.ac.uk
    Issue Date
    2000-01-15
    
    Metadata
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    Abstract
    Tumour resistance to methylating agents is linked to expression of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (ATase). There is considerable interest in improving the efficacy of O(6)-alkylating chemotherapy by prior depletion of ATase. We have tested the ability of a modified guanine base, O(6)-(4-bromothenyl)guanine (4BTG), to inactivate ATase and to enhance the anti-tumour effect of temozolomide in an animal model system. A375M human melanoma xenografts were established in the flanks of nude mice. ATase depletion after a single dose of 4BTG or O(6)-BG (20 mg/kg i.p.) was determined over a 24 hr period. Subsequently, we tested the effect of 4BTG (20 mg/kg i.p. daily) and/or temozolomide (80-175 mg/kg i.p. daily) over a 5-day schedule on tumour growth. 4BTG was an effective inactivator of ATase in tumour, producing complete depletion within 2 hr of dosing. Furthermore, it enhanced the tumour growth delay achieved with temozolomide, increasing the tumour quintupling time by 8.7 days (95% confidence interval 6.1-11.3 days, p < 0.0001). Whilst the delay in tumour growth was indistinguishable from that observed with O(6)-benzylguanine (O(6)-BG) and temozolomide, the 4BTG combination resulted in considerably less toxicity (0/9 vs. 2/9 deaths; 6.84% weight loss vs. 9.48%, p = 0.019). 4BTG is a potent inactivator of ATase and enhances the therapeutic ratio of temozolomide in this model system to a greater extent than O(6)-BG.
    Citation
    O(6)-(4-bromothenyl)guanine improves the therapeutic index of temozolomide against A375M melanoma xenografts. 2000, 85 (2):248-52 Int J Cancer
    Journal
    International Journal of Cancer
    URI
    http://hdl.handle.net/10541/108144
    PubMed ID
    10629085
    Type
    Article
    Language
    en
    ISSN
    0020-7136
    Collections
    All Christie Publications
    All Paterson Institute for Cancer Research

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