Toxicity, mutation frequency and mutation spectrum induced by dacarbazine in CHO cells expressing different levels of O(6)-methylguanine-DNA methyltransferase.
The toxicity and mutagenicity (including the mutation spectrum induced) of dacarbazine, a methylating cytostatic drug, was examined in CHO cells expressing different levels of the repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT). Expression of low or high levels of a transfected human MGMT gene under the control of the metallothionein promoter protected the cells against dacarbazine-induced toxicity and mutagenesis. In the absence of MGMT expression, the mutation spectrum in the HPRT locus was dominated by GC-->AT transitions (mostly found at 5'Pu-G sequences), while there were also a few AT-->GC transitions. Expression MGMT was associated with a substantial decrease of GC-->AT mutations, suggesting that these mutations arose primarily via O(6)-methylguanine. These data illustrate the important role of the latter lesion in the drug's mutagenic and cytotoxic activity.
Psaroudi
M C
MC
National Hellenic Research Foundation, Institute of Biological Research and Biotechnology, 48 Vassileos Constantinou Ave., Athens, Greece.
Kyrtopoulos
S A
SA
D019943:Amino Acid Substitution; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D019175:DNA Methylation / Q000187:drug effects; D004252:DNA Mutational Analysis; D003606:Dacarbazine / Q000633:toxicity*; D004790:Enzyme Induction; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000187:drug effects / Q000235:genetics; D008110:Liver Extracts / Q000494:pharmacology; D008297:Male; D008770:Methylnitrosourea / Q000633:toxicity; D009154:Mutation / Q000187:drug effects; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D051381:Rats; D017207:Rats, Sprague-Dawley
D008110:Liver Extracts; D006147:Guanine; D008770:Methylnitrosourea; D003606:Dacarbazine; C008449:O-(6)-methylguanine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D007041:Hypoxanthine Phosphoribosyltransferase