O6-alkylguanine-DNA alkyltransferase attenuates triazene-induced cytotoxicity and tumor cell immunogenicity in murine L1210 leukemia.

2.50
Hdl Handle:
http://hdl.handle.net/10541/97974
Title:
O6-alkylguanine-DNA alkyltransferase attenuates triazene-induced cytotoxicity and tumor cell immunogenicity in murine L1210 leukemia.
Authors:
Graziani, G; Faraoni, I; Grohmann, U; Bianchi, R; Binaglia, L; Margison, Geoffrey P; Watson, Amanda J; Orlando, L; Bonmassar, E; D'Atri, S
Abstract:
Methylating 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.
Affiliation:
Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Italy.
Citation:
O6-alkylguanine-DNA alkyltransferase attenuates triazene-induced cytotoxicity and tumor cell immunogenicity in murine L1210 leukemia. 1995, 55 (24):6231-6 Cancer Res.
Journal:
Cancer Research
Issue Date:
15-Dec-1995
URI:
http://hdl.handle.net/10541/97974
PubMed ID:
8521419
Type:
Article
Language:
en
ISSN:
0008-5472
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorGraziani, Gen
dc.contributor.authorFaraoni, Ien
dc.contributor.authorGrohmann, Uen
dc.contributor.authorBianchi, Ren
dc.contributor.authorBinaglia, Len
dc.contributor.authorMargison, Geoffrey Pen
dc.contributor.authorWatson, Amanda Jen
dc.contributor.authorOrlando, Len
dc.contributor.authorBonmassar, Een
dc.contributor.authorD'Atri, Sen
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.en
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

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