Antitumor imidazotetrazines--XV. Role of guanine O6 alkylation in the mechanism of cytotoxicity of imidazotetrazinones.
Cell lines with constitutive levels of the DNA repair protein O6-methylguanine-DNA methyltransferase (O6MeGMT) (Mer+ phenotype) were less sensitive to the cytotoxic effects of the imidazotetrazinone mitozolomide and the methyl analogue (CCRG 81045) than cells lacking the repair enzyme (Mer-). In contrast neither chlorambucil or the ethylimidazotetrazinone (CCRG 82019) showed differential toxicity between Mer+ and Mer- cell lines. When Mer+ cell lines were incubated with the free base O6-methylguanine (O6MeG) for 16 hr there was a depletion of O6MeGMT, which was dose-related. Such cells showed an increased sensitivity to both mitozolamide and CCRG 81045, but not to CCRG 82019. The only Mer+ cell line not showing increased sensitization with O6MeG pretreatment was Raji, where O6MeGMT was shown to reappear after addition of CCRG 81045. These results suggest that the chloroethyl and methylimidazole-triazinones are similar to the nitrosoureas and triazenes in that cytotoxicity correlates with alkylation of the O6-position of guanine, while the ethyl analogues appear to produce an alternate cytotoxic lesion.
Tisdale
M J
MJ
D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002460:Cell Line; D002699:Chlorambucil / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy; D004260:DNA Repair; D003606:Dacarbazine / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D008223:Lymphoma / Q000188:drug therapy; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D009588:Nitrogen Mustard Compounds / Q000627:therapeutic use*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D010641:Phenotype; D000077204:Temozolomide
D000970:Antineoplastic Agents; D007093:Imidazoles; D009588:Nitrogen Mustard Compounds; D002699:Chlorambucil; D006147:Guanine; D003606:Dacarbazine; C047398:ethazolastone; C008449:O-(6)-methylguanine; C040369:mitozolomide; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide