Document Detail


Effect of O6-benzylguanine on alkylating agent-induced toxicity and mutagenicity. In Chinese hamster ovary cells expressing wild-type and mutant O6-alkylguanine-DNA alkyltransferases.
MedLine Citation:
PMID:  11034089     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) has been shown to protect cells from the toxic and mutagenic effect of alkylating agents by removing lesions from the O6 position of guanine. O6-Benzylguanine (BG) is a potent inactivator of AGT, resulting in an increase in the sensitivity of cells to the toxic effects of chemotherapeutic alkylating agents. Chinese hamster ovary (CHO) cells and CHO cells transfected with wild-type AGT (CHOWTAGT) and a mutant AGT [P138 M/V139I/P140K (CHOMIK)] known to be resistant to BG were treated with BG and various alkylating agents. BG treatment alone dramatically decreased AGT activity in CHOWTAGT cells but resulted in no depletion in AGT activity in CHOMIK cells. In the absence of AGT, these cells are highly sensitive to the toxic and mutagenic effects of temozolomide and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and no further sensitization occurs in the presence of BG. In contrast, CHOWTAGT cells are resistant to temozolomide and BCNU, and treatment with BG resulted in a significantly higher cell killing and mutation frequency. CHOMIK cells were completely resistant to temozolomide or BCNU in the presence and absence of BG. Both cell killing and mutation frequency of 4-hydroperoxycyclophosphamide (4-HC) in CHO, CHOWTAGT, and CHOMIK cells were increased in the presence of BG. 4-HC generates two active metabolites, phosphoramide mustard (PM) and acrolein. BG had no effect on 4hydroperoxydidechlorocyclophosphamide (which generates acrolein and a nonalkylating form of PM) in CHO cells and CHOMIK cells, but enhancement of toxicity was observed with PM in both these cell lines. Therefore, we attribute the enhancement to the PM metabolite of 4-HC. Our results demonstrate that wild-type AGT plays an important role in protecting against the toxic and mutagenic effect of O6 alkylating agents and that a mutant AGT resistant to inactivation by BG effectively prevents BG-enhanced toxicity and mutagenicity induced by these agents. Expression of the AGT protein contributes to resistance of 4-HC. BG also enhances the toxicity of 4-HC and PM by a mechanism that may not involve the AGT repair protein.
Authors:
Y Cai; M H Wu; M Xu-Welliver; A E Pegg; S M Ludeman; M E Dolan
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  60     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2000 Oct 
Date Detail:
Created Date:  2000-10-16     Completed Date:  2000-10-27     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  5464-9     Citation Subset:  IM    
Affiliation:
Department of Medicine University of Chicago, Illinois 60637, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents, Alkylating / toxicity*
CHO Cells / drug effects,  enzymology
Carmustine / toxicity
Cricetinae
Cyclophosphamide / analogs & derivatives*,  toxicity
Dacarbazine / analogs & derivatives*,  toxicity
Drug Interactions
Enzyme Inhibitors / toxicity*
Guanine / analogs & derivatives*,  toxicity*
Mutagenicity Tests
Mutagens / toxicity
O(6)-Methylguanine-DNA Methyltransferase / antagonists & inhibitors,  genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
CA16783/CA/NCI NIH HHS; CA57725/CA/NCI NIH HHS; CA81485/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Alkylating; 0/Enzyme Inhibitors; 0/Mutagens; 154-93-8/Carmustine; 19916-73-5/O(6)-benzylguanine; 39800-16-3/perfosfamide; 4342-03-4/Dacarbazine; 50-18-0/Cyclophosphamide; 73-40-5/Guanine; 85622-93-1/temozolomide; EC 2.1.1.63/O(6)-Methylguanine-DNA Methyltransferase

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