The production of hydroxyl radical by tallysomycin and copper(II)

Tallysomycin is an antitumor antibiotic that is structurally related to bleomycin. The mechanism of action of tallysomycin appears to be similar to that of bleomycin. Bleomycin induces strand scission of purified isolated DNA [ l--5]. Bleomycin has also been shown to produce breakage of intracellular DNA [5,6]. Iron(H) appears to be associated with the mechanism of action of bleomycin. The following model for the action of bleomycin has been proposed [ 11. Bleomycin can bind to DNA. Fe(H) can then attach to the bleomycin to form a ternary complex. This complex, in the presence of oxygen, can then produce a species which degrades DNA. We have recently shown that bleomycin and Fe(H) produces the hydroxyl radical [7]. Because of the high reactivity of ‘OH, it is likely that this radical is responsible for the toxicity of bleomycin. Tallysomycin, a third generation bleomycin analogue, has been found to be more potent than bleomycin in the Walker 256 carcinoma and the P-388 leukemia tumor systems [S], as well as in a variety of bacteria and fungi [9]. Antitumor activity has also been observed for other tumor systems [9]. The mechanism of action of tallysomycin appears to be similar to that of bleomycin in that it produces strand breaks in purified isolated DNA and intracellular DNA similar to bleomycin [5]. However, the increased efficacy of tallysomycin to bleomycin could not be correlated with the breakage of DNA in vitro [S]. It was also observed that the concentration of ferrous ion appeared not to be a factor in the greater breakage of DNA observed for bleomycin over that of tallysomycin.