Chromosome damage in the bone marrow of mice treated with the methylating agents methyl methanesulphonate and N-methyl-N-nitrosourea in the presence or absence of caffeine, and its relationship with thymoma induction.
A single dose (0.8 mmole/kg) of N-methyl-N-nitrosourea (MNUA) causes significantly more chromosome damage in the bone marrow of mice than a dose of equal toxicity to the animals, (1.1 mmole/kg) of methyl methanesulphonate (MMS) 6, 24 and 48 h after treatment. At these doses both agents alkylate bone-marrow DNA to similar extents, but only MNUA induces thymic lymphomata. The greater chromosome-damaging effects of MNUA are ascribed to the known differences in the pattern of DNA alkylation by each agent, in particular the much higher levels of O-6 methylguanine and phosphotriesters produced by MNUA. The greater chromosome-damaging effect of MNUA may account for its higher toxicity to the bone marrow which in turn may be a significant factor in the induction of thymomata. The enhancement by caffeine of chromosome damage seen particularly 48 h after MMS-treatment suggests that post-replication repair protects cells from the effects of DNA-methylation in vivo.
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000648:ultrastructure; D001854:Bone Marrow Cells; D002110:Caffeine / Q000494:pharmacology*; D002869:Chromosome Aberrations; D002872:Chromosome Deletion / Q000187:drug effects; D002875:Chromosomes / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D008698:Mesylates / Q000494:pharmacology*; D008741:Methyl Methanesulfonate / Q000494:pharmacology*; D008770:Methylnitrosourea / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens; D009607:Nitrosourea Compounds / Q000494:pharmacology*; D013047:Specific Pathogen-Free Organisms; D013945:Thymoma / Q000139:chemically induced*; D013953:Thymus Neoplasms / Q000139:chemically induced*
D008698:Mesylates; D009153:Mutagens; D009607:Nitrosourea Compounds; D002110:Caffeine; D008770:Methylnitrosourea; D008741:Methyl Methanesulfonate