In vivo administration of O(6)-benzylguanine does not influence apoptosis or mutation frequency following DNA damage in the murine intestine, but does inhibit P450-dependent activation of dacarbazine.

2.50
Hdl Handle:
http://hdl.handle.net/10541/86189
Title:
In vivo administration of O(6)-benzylguanine does not influence apoptosis or mutation frequency following DNA damage in the murine intestine, but does inhibit P450-dependent activation of dacarbazine.
Authors:
Toft, Neil J; Sansom, Owen J; Brookes, Roger A; Arends, Mark J; Wood, Michelle; Margison, Geoffrey P; Winton, Douglas J; Clarke, Alan R
Abstract:
Clinically relevant cancer chemotherapeutic alkylating agents such as temozolomide and dacarbazine induce apoptosis and are mutagenic via the formation of O(6)-alkylguanine adducts in DNA. The DNA repair protein O(6)-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 O(6)-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.
Affiliation:
Department of Pathology, University of Edinburgh, Edinburgh EH8 9AG, UK.
Citation:
In vivo administration of O(6)-benzylguanine does not influence apoptosis or mutation frequency following DNA damage in the murine intestine, but does inhibit P450-dependent activation of dacarbazine. 2000, 21 (4):593-8 Carcinogenesis
Journal:
Carcinogenesis
Issue Date:
Apr-2000
URI:
http://hdl.handle.net/10541/86189
DOI:
10.1093/carcin/21.4.593
PubMed ID:
10753191
Type:
Article
Language:
en
ISSN:
0143-3334
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorToft, Neil Jen
dc.contributor.authorSansom, Owen Jen
dc.contributor.authorBrookes, Roger Aen
dc.contributor.authorArends, Mark Jen
dc.contributor.authorWood, Michelleen
dc.contributor.authorMargison, Geoffrey Pen
dc.contributor.authorWinton, Douglas Jen
dc.contributor.authorClarke, Alan Ren
dc.date.accessioned2009-11-13T15:45:09Z-
dc.date.available2009-11-13T15:45:09Z-
dc.date.issued2000-04-
dc.identifier.citationIn vivo administration of O(6)-benzylguanine does not influence apoptosis or mutation frequency following DNA damage in the murine intestine, but does inhibit P450-dependent activation of dacarbazine. 2000, 21 (4):593-8 Carcinogenesisen
dc.identifier.issn0143-3334-
dc.identifier.pmid10753191-
dc.identifier.doi10.1093/carcin/21.4.593-
dc.identifier.urihttp://hdl.handle.net/10541/86189-
dc.description.abstractClinically relevant cancer chemotherapeutic alkylating agents such as temozolomide and dacarbazine induce apoptosis and are mutagenic via the formation of O(6)-alkylguanine adducts in DNA. The DNA repair protein O(6)-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 O(6)-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.en
dc.language.isoenen
dc.subject.meshAnimals-
dc.subject.meshAntineoplastic Agents, Alkylating-
dc.subject.meshApoptosis-
dc.subject.meshBiotransformation-
dc.subject.meshCisplatin-
dc.subject.meshCytochrome P-450 Enzyme System-
dc.subject.meshDNA Damage-
dc.subject.meshDacarbazine-
dc.subject.meshEnzyme Inhibitors-
dc.subject.meshGuanine-
dc.subject.meshIntestine, Small-
dc.subject.meshMethylnitrosourea-
dc.subject.meshMice-
dc.subject.meshMutation-
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase-
dc.titleIn vivo administration of O(6)-benzylguanine does not influence apoptosis or mutation frequency following DNA damage in the murine intestine, but does inhibit P450-dependent activation of dacarbazine.en
dc.typeArticleen
dc.contributor.departmentDepartment of Pathology, University of Edinburgh, Edinburgh EH8 9AG, UK.en
dc.identifier.journalCarcinogenesisen
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