Abstract
The antitumor anthracycline doxorubicin induces a dose-related cardiotoxicity that correlates with the myocardial levels of its secondary alcohol metabolite doxorubicinol. Combining doxorubicin with taxanes such as paclitaxel or docetaxel may aggravate cardiotoxicity, presumably because the taxanes cause an allosteric-like stimulation of cytoplasmic aldehyde reductases that convert doxorubicin to doxorubicinol in the heart. A less severe aggravation of cardiotoxicity was observed on combining taxanes with epirubicin, a closely related analog of doxorubicin; therefore, we characterized whether the cardiac tolerability of epirubicin-taxane therapies could be due to a defective taxane stimulation of the conversion of epirubicin to its secondary alcohol metabolite epirubicinol. Comparisons between doxorubicin and epirubicin in isolated human heart cytosol showed that epirubicin exhibited a lower Vmax/Km value for reaction with aldehyde reductases and a defective stimulation of epirubicinol formation by paclitaxel or docetaxel. A similar pattern occurred in the soluble fraction of human myocardial strips incubated in plasma with anthracyclines and paclitaxel or docetaxel, formulated in their clinical vehicles Cremophor EL or polysorbate 80. Doxorubicin, but not epirubicin, was also able to generate reactive oxygen species in the membrane fraction of myocardial strips; however, the levels of doxorubicin-derived reactive oxygen species were not further augmented by paclitaxel. These results support the notion that taxanes might aggravate the cardiotoxicity of doxorubicin through a specific stimulation of doxorubicinol formation. The failure of paclitaxel or docetaxel to stimulate epirubicinol formation therefore uncovers an important determinant of the improved cardiac tolerability of epirubicin-taxane combinations.
Footnotes
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↵1 The small size of human myocardial strips did not allow for an accurate subcellular fractionation and direct measurements of epirubicin in one organelle or another. The distribution of epirubicin to acidic vesicles rather than mitochondria was demonstrated by monitoring ROS formation in the absence or presence of bafilomycin A1 and by confocal microscopy visualization of epirubicin, mitochondria, and acidic vesicles in H9c2 cardiomyocytes (Salvatorelli et al., 2006a).
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↵2 The anomalous distribution of epirubicin to acidic organelles probably was favored by its slightly higher lipophilicity and consequent facilitated diffusion in the vacuoles, followed by protonation of the amino group of daunosamine and vacuolar retention of the drug (Wielinga et al., 2000; Salvatorelli et al., 2006a).
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This work was supported by Associazione Italiana Ricerca sul Cancro and Ministero dell' Universita' e Ricerca Scientifica e Tecnologica (Cofin 2004, FIRB RBNE 014HJ3–002, and Center of Excellence on Aging at the University of Chieti) (to G.M.).
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E.S. and P.M. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.116160.
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ABBREVIATIONS: CHF, congestive heart failure; ROS, reactive oxygen species; EBPC, ethyl-1-benzyl-3-hydroxy-2(5H)-oxopyrrole-4-carboxylate; AL1576, 2,7-difluorospirofluorene-9,5′-imidazolidine-2′,4′-dione; DCFH-(DA), dichlorofluorescin-(diacetate); DCF, dichlorofluorescein; HPLC, high-performance liquid chromatography.
- Received October 25, 2006.
- Accepted November 21, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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