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Paclitaxel and Docetaxel Enhance the Metabolism of Doxorubicin to Toxic Species in Human Myocardium
Ist Teil von
Clinical cancer research, 2001-06, Vol.7 (6), p.1511-1515
Ort / Verlag
Philadelphia, PA: American Association for Cancer Research
Erscheinungsjahr
2001
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
Doxorubicin cardiotoxicity is a multifactorial process in which the alcohol metabolite doxorubicinol mediates the transition
from reversible to irreversible 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
paclitaxel. Specimens of human myocardium from patients undergoing bypass surgery were processed to obtain cytosolic fractions
in which doxorubicin was converted to doxorubicinol by NADPH-dependent aldo/keto or carbonyl reductases. In this model, clinically
relevant concentrations of paclitaxel (1–2.5 μ m ) increased doxorubicinol formation by mechanisms consistent with allosteric modulation of the reductases. Stimulation was
observed over a broad range of basal enzymatic activity, and was accompanied by a similar pattern of enhanced formation of
doxorubicinol aglycone, a metabolite potentially involved in the reversible phase of cardiotoxicity. The closely related analogue
docetaxel had effects similar to paclitaxel, but increased doxorubicinol formation over a narrower range of enzymatic activity.
The unrelated tubulin-active alkaloid vinorelbine had no effect. These results demonstrate that taxanes have a unique potential
for enhancing doxorubicin metabolism to toxic species in human myocardium. The effects on doxorubicinol formation provide
clues to explain the clinical pattern of doxorubicin-paclitaxel cardiotoxicity and also caution against the potential toxicity
of combining docetaxel with high cumulative doses of doxorubicin.