O6-alkylguanine-DNA alkyltransferase attenuates triazene-induced cytotoxicity and tumor cell immunogenicity in murine L1210 leukemia.
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.
Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Italy.
G
G
Graziani
I
I
Faraoni
U
U
Grohmann
R
R
Bianchi
L
L
Binaglia
G P
GP
Margison
A J
AJ
Watson
L
L
Orlando
E
E
Bonmassar
S
S
D'Atri
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D001483:Base Sequence; D004249:DNA Damage; D017931:DNA Primers / Q000737:chemistry; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000633:toxicity; D006801:Humans; D007939:Leukemia L1210 / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D009588:Nitrogen Mustard Compounds / Q000633:toxicity; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide; D014162:Transfection; D014227:Triazines / Q000633:toxicity*; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D017931:DNA Primers; D009588:Nitrogen Mustard Compounds; D014227:Triazines; D003606:Dacarbazine; C040369:mitozolomide; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide