Time-dependent modifications of ferric-Adriamycin

The biological and chemical properties of the ferric-Adriamycin complex changed with time after its preparation. Our experiments demonstrated that the toxicity of the iron-chelate in mice decreased as a function of its age. The reduced toxicity can be correlated with changes in the difference spectrum of ferric-Adriamycin vs Adriamycin^® (ADR), where a peak around 610 nm shifted to the 570 nm region. When ferric-Adriamycin "aged", the affinity of the drug for iron increased. Concurrently, the redox properties of the chelate changed, such that the bound iron was no longer reduced by glutathione or cysteine. The time-dependent changes observed did not involve the formation of polynuclear iron, as shown by electron spin resonance. Thin-layer chromatography showed that ADR undergoes accelerated degradation in the presence of iron. The iron-catalyzed degradation was oxygen independent. The changes evolving in the spectral and chemical properties of the chelate were shown to stem from transfer of the iron from ADR to one of the degradation products.