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dc.contributor.authorGraziani, G
dc.contributor.authorFaraoni, I
dc.contributor.authorGrohmann, U
dc.contributor.authorBianchi, R
dc.contributor.authorBinaglia, L
dc.contributor.authorMargison, Geoffrey P
dc.contributor.authorWatson, Amanda J
dc.contributor.authorOrlando, L
dc.contributor.authorBonmassar, E
dc.contributor.authorD'Atri, S
dc.date.accessioned2010-05-05T12:10:32Z
dc.date.available2010-05-05T12:10:32Z
dc.date.issued1995-12-15
dc.identifier.citationO6-alkylguanine-DNA alkyltransferase attenuates triazene-induced cytotoxicity and tumor cell immunogenicity in murine L1210 leukemia. 1995, 55 (24):6231-6 Cancer Res.en
dc.identifier.issn0008-5472
dc.identifier.pmid8521419
dc.identifier.urihttp://hdl.handle.net/10541/97974
dc.description.abstractMethylating and chloroethylating triazene compounds (TZCs) are effective antitumor agents in murine leukemias and can induce the appearance of novel antigens in leukemic cells (chemical xenogenization). Recently, it has been shown that TZCs might have a role in the treatment of patients affected by acute myelogenous leukemias that express low levels of the DNA repair enzyme, O6-alkylguanine-DNA alkyltransferase (OGAT). In this report, we have evaluated the role of this DNA repair enzyme in the leukemic cell response to the xenogenizing and cytotoxic properties of TZCs. OGAT-deficient murine leukemic L1210 cells were transfected with a recombinant ecotropic retrovirus containing the coding region for the human OGAT protein. Selected clones expressed the human OGAT transcript and had greatly increased OGAT activity. Compared to OGAT-deficient cells, OGAT-expressing cells were considerably more resistant to the xenogenizing properties of 1-(p-chlorophenyl)-3,3- dimethyl-triazene, measured in terms of leukemia graft rejection, and were less susceptible to the cytotoxic activity of the TZCs 8-carbamoyl-3-methyl-imidazo [5,1-d]-1,2,3,5-tetrazin-4(3H)-one and 8-carbamoyl-3-(2-chloroethyl)imidazo [5,1-d]-1,2,3,5-tetrazin-4(3H)-one. These data suggest that methylation of the O6 position of guanine is involved in the appearance of increased tumor immunogenicity after exposure to methylating TZC and that OGAT is able, at least in part, to counteract the cytotoxic effects of methylating and chloroethylating agents.
dc.language.isoenen
dc.subjectLeukaemia L1210en
dc.subjectCultured Tumour Cellsen
dc.subject.meshAnimals
dc.subject.meshAntineoplastic Agents, Alkylating
dc.subject.meshBase Sequence
dc.subject.meshDNA Damage
dc.subject.meshDNA Primers
dc.subject.meshDacarbazine
dc.subject.meshHumans
dc.subject.meshLeukemia L1210
dc.subject.meshMethyltransferases
dc.subject.meshMice
dc.subject.meshMice, Inbred BALB C
dc.subject.meshMice, Inbred DBA
dc.subject.meshMolecular Sequence Data
dc.subject.meshNitrogen Mustard Compounds
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase
dc.subject.meshTransfection
dc.subject.meshTriazines
dc.subject.meshTumor Cells, Cultured
dc.titleO6-alkylguanine-DNA alkyltransferase attenuates triazene-induced cytotoxicity and tumor cell immunogenicity in murine L1210 leukemia.en
dc.typeArticleen
dc.contributor.departmentDepartment of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Italy.en
dc.identifier.journalCancer Researchen
html.description.abstractMethylating and chloroethylating triazene compounds (TZCs) are effective antitumor agents in murine leukemias and can induce the appearance of novel antigens in leukemic cells (chemical xenogenization). Recently, it has been shown that TZCs might have a role in the treatment of patients affected by acute myelogenous leukemias that express low levels of the DNA repair enzyme, O6-alkylguanine-DNA alkyltransferase (OGAT). In this report, we have evaluated the role of this DNA repair enzyme in the leukemic cell response to the xenogenizing and cytotoxic properties of TZCs. OGAT-deficient murine leukemic L1210 cells were transfected with a recombinant ecotropic retrovirus containing the coding region for the human OGAT protein. Selected clones expressed the human OGAT transcript and had greatly increased OGAT activity. Compared to OGAT-deficient cells, OGAT-expressing cells were considerably more resistant to the xenogenizing properties of 1-(p-chlorophenyl)-3,3- dimethyl-triazene, measured in terms of leukemia graft rejection, and were less susceptible to the cytotoxic activity of the TZCs 8-carbamoyl-3-methyl-imidazo [5,1-d]-1,2,3,5-tetrazin-4(3H)-one and 8-carbamoyl-3-(2-chloroethyl)imidazo [5,1-d]-1,2,3,5-tetrazin-4(3H)-one. These data suggest that methylation of the O6 position of guanine is involved in the appearance of increased tumor immunogenicity after exposure to methylating TZC and that OGAT is able, at least in part, to counteract the cytotoxic effects of methylating and chloroethylating agents.


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