Interaction of anthracycline antibiotics with human neutrophils: superoxide production, free radical formation and intracellular penetration.
Human neutrophils exposed to 10(-4) M doxorubicin and the derivatives epirubicin and thepirubicin revealed a different intracellular penetration and distribution pattern as demonstrated by fluorescence microscopy and fluorimetric determination of drug intracellular concentration. While doxorubicin was found to be a potent inducer of superoxide generation from resting cells, epirubicin exhibited less superoxide-inducing power. Thepirubicin on the contrary did not show any superoxide-inducing effect. Moreover the anthracyclines tested all inhibited the phorbol ester-stimulated chemiluminescent response to the same extent, which suggested a common target for the drug action. Anthracycline-stimulated superoxide production seems to correlate with the cardiotoxic effects. The most cardiotoxic drug, doxorubicin, is the most potent inducer of superoxide generation, while epirubicin, which is less cardiotoxic, has a relatively limited effect on superoxide production. Thepirubicin which has been shown not to induce delayed cardiomyopathy has no effect on superoxide release from the cells.
D000903:Antibiotics, Antineoplastic; D002463:Cell Membrane Permeability; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D015251:Epirubicin; D005609:Free Radicals; D006801:Humans; D066298:In Vitro Techniques; D008163:Luminescent Measurements; D009279:Naphthacenes / Q000378:metabolism / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000096:biosynthesis*
D000903:Antibiotics, Antineoplastic; D005609:Free Radicals; D009279:Naphthacenes; D013481:Superoxides; D015251:Epirubicin; D004317:Doxorubicin; C027260:pirarubicin