Paclitaxel and docetaxel enhance the metabolism of doxorubicin to toxic species in human myocardium

Doxorubicin cardiotoxicity is a multifactorial process in which the alcohol metabolite doxorubicinol mediates the transition from reversible to irreve rsible damage, We investigated whether the tubulin-active taxane paclitaxel increases conversion of doxorubicin to doxorubicinol, thus explaining the high incidence of congestive heart failure when doxorubicin is used with pa clitaxel, Specimens of human myocardium from patients undergoing bypass sur gery were processed to obtain cytosolic fractions in which doxorubicin was converted to doxorubicinol by NADPH-dependent aldo/keto or carbonyl reducta ses, In this model, clinically relevant concentrations of paclitaxel (1-2.5 muM) increased doxorubicinol formation by mechanisms consistent with allos teric modulation of the reductases. Stimulation was observed over a broad r ange of basal enzymatic activity, and was accompanied by a similar pattern of enhanced formation of doxorubicinol aglycone, a metabolite potentially i nvolved in the reversible phase of cardiotoxicity, The closely related anal ogue docetaxel had effects similar to paclitaxcel, but increased doxorubici nol formation over narrower range of enzymatic activity. The unrelated tubu lin-active alkaloid vinorelbine had no effect. These results demonstrate th at taxanes have a unique potential for enhancing doxorubicin metabolism to toxic species in human myocardium. The effects on doxorubicinol formation p rovide clues to explain the clinical pattern of doxorubicin-paclitaxel card iotoxicity and also caution against the potential toxicity of combining doc etaxel with high cumulative doses of doxorubicin.