Journal Article

<i>In vivo</i> administration of <i>O</i><sup>6</sup>-benzylguanine does not influence apoptosis or mutation frequency following DNA damage in the murine intestine, but does inhibit P450-dependent activation of dacarbazine

Neil J. Toft, Owen J. Sansom, Roger A. Brookes, Mark J. Arends, Michelle Wood, Geoffrey P. Margison, Douglas J. Winton and Alan R. Clarke

in Carcinogenesis

Volume 21, issue 4, pages 593-598
Published in print April 2000 | ISSN: 0143-3334
Published online April 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.4.593
In vivo administration of O6-benzylguanine does not influence apoptosis or mutation frequency following DNA damage in the murine intestine, but does inhibit P450-dependent activation of dacarbazine

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Clinically relevant cancer chemotherapeutic alkylating agents such as temozolomide and dacarbazine induce apoptosis and are mutagenic via the formation of O6-alkylguanine adducts in DNA. The DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) functions by dealkylating such adducts and can thus prevent apoptosis and mutagenesis. In attempts to maximize the clinical effectiveness of these alkylating agents, inhibitors of AGT such as O6-benzylguanine (BeG) have been developed. We show here that within murine small intestinal crypt cells, BeG administration does not alter the apoptotic response to the direct-acting methylating agents N-methyl-N-nitrosurea (MNU), temozolomide and N-methyl-N′-nitro-N-nitrosoguanidine. Furthermore, we show that BeG pretreatment fails to elevate the mutation frequency at the murine Dlb-1 locus following exposure to MNU. Consistent with these results, we show that intestinal AGT activity is effectively abolished by administration of 100 mg/kg temozolomide, even in the absence of BeG. In contrast, pretreatment with BeG transiently abolished the apoptotic response to the methylating prodrug dacarbazine. Activation of dacarbazine to its reactive intermediate has previously been shown to be cytochrome P450 dependent and we show here that pretreatment of mice with the cytochrome P450 inhibitor metyrapone also inhibits dacarbazine-induced apoptosis. Thus BeG increases neither the prevalence of apoptosis nor mutation frequency in the murine small intestine, but is capable of inhibiting P450-dependent prodrug activation. The positive implication from this study is that BeG treatment may not exacerbate the toxic and mutagenic effects of methylating agents within normal cells, although it may engender other adverse reactions through the suppression of cytochrome P450-dependent processes.

Keywords: AGT, O6-alkylguanine-DNA alkyltransferase; BeG, O6-benzylguanine; DBA, Dolichos biflorus agglutinin; dacarbazine, 5-(3,3-dimethyltriazen-1-yl)imidazole-4-carboxamide; MITC, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide; MNNG, N-methyl-N′-nitro-N-nitrosoguanidine; MNU, N-methyl-N-nitrosurea; PBS, phosphate-buffered saline.

Journal Article.  4651 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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