DNA sequence‐specific adducts of adriamycin and mitomycin C

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Abstract
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+, Cu2+ 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.