DNA sequence-specific adducts of adriamycin and mitomycin C.
Adriamycin and mitomycin C were reduced by xanthine oxidase/NADH in the presence of a DNA template comprising a stable initiated ternary transcription complex derived from the lac UV5 promoter. Subsequent elongation of the transcription complex treated with mitomycin C revealed high levels of terminated transcripts one nucleotide prior to G residues on the coding strand (i.e. at X of XpC sequences of the non-coding strand). Lower levels of termination occurred with adriamycin, and these were also one nucleotide prior to G residues of the coding strand, but with greater sequence specificity since they were observed mainly at G of GpC sequences of the non-coding strand. The same sites were also observed with adriamycin in the absence of reducing conditions and the level of termination at these sites was enhanced up to 10-fold by Fe2+ and Fe3+, but not by Cu2+, Zn2+, Co2+ or Ni2+. These results suggest that an iron-adriamycin complex with DNA is highly sequence-specific and results in adducts, similar to those of mitomycin C, which can terminate the transcription process. Such a mechanism offers new insights into the possible mode of action of anthracyclines.
Phillips
D R
DR
Department of Biochemistry, La Trobe University, Bundoora, Victoria, Australia.
White
R J
RJ
Cullinane
C
C
D001483:Base Sequence; D002412:Cations; D004247:DNA / Q000378:metabolism*; D004317:Doxorubicin / Q000378:metabolism* / Q000494:pharmacology; D005290:Ferric Compounds / Q000494:pharmacology; D005296:Ferrous Compounds / Q000494:pharmacology; D016685:Mitomycin; D008937:Mitomycins / Q000378:metabolism* / Q000494:pharmacology; D008969:Molecular Sequence Data; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic / Q000187:drug effects; D014969:Xanthine Oxidase / Q000378:metabolism
D002412:Cations; D005290:Ferric Compounds; D005296:Ferrous Compounds; D008937:Mitomycins; D009243:NAD; D016685:Mitomycin; D004317:Doxorubicin; D004247:DNA; D014969:Xanthine Oxidase