In vitro and in vivo methazolastone-induced DNA damage and repair in L-1210 leukemia sensitive and resistant to chloroethylnitrosoureas.
DNA damage caused by methazolastone [an analogue of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide which does not require metabolic activation] was investigated in L-1210 leukemia which is sensitive to this drug and in a L-1210 subline [L-1210/N,N-bis(2-chloroethyl)-N-nitrosourea (BCNU)] which is resistant to both chloroethylnitrosoureas and methyltriazenes. Both in vitro and in vivo metazolastone caused formation of DNA alkali-labile sites (assessed by alkaline elution techniques) which were present in similar amounts and repaired at a similar rate in L-1210 and L-1210/BCNU. This suggests that these lesions are not crucial to methyltriazenes activity. DNA alkali-labile sites may be due to the removal of 7-methylguanine by 7-methylguanine-DNA glycosylase which showed the same activity in L-1210 and L-1210/BCNU. Flow cytometry studies revealed that in L-1210 but not in L-1210/BCNU methazolastone induced an arrest of cells in SL-G2-M phases. This blockade was delayed, occurring after at least two cell divisions after drug treatment and therefore appeared temporally unrelated to the presence of DNA alkali-labile sites. There was three times more O6-methylguanine-DNA methyltransferase in L-1210/BCNU than in L-1210 suggesting that methylation of O6-guanine is an important lesion for methyltriazenes activity and resistance to this drug may be linked to its repair.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002330:Carmustine / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000032:analysis; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004351:Drug Resistance; D005434:Flow Cytometry; D007939:Leukemia L1210 / Q000188:drug therapy*; D008745:Methylation; D008780:Methyltransferases / Q000032:analysis; D051379:Mice; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D003606:Dacarbazine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine; D000077204:Temozolomide