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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Defective Taxane Stimulation of Epirubicinol Formation in the Human Heart: Insight into the Cardiac Tolerability of Epirubicin-Taxane Chemotherapies

Department of Drug Sciences and Center of Excellence on Aging, G. d'Annunzio University School of Medicine, Chieti, Italy (E.S., P.M., G.M.); and Division of Medical Oncology A, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy (L.G.)

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 V_max/K_m 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.

Address correspondence to: Dr. Giorgio Minotti, Department of Drug Sciences and Center of Excellence on Aging, G. d'Annunzio University School of Medicine, Via dei Vestini, 66013 Chieti, Italy. E-mail: gminotti{at}unich.it

This article has been cited by other articles:

				L. Gianni, E. H. Herman, S. E. Lipshultz, G. Minotti, N. Sarvazyan, and D. B. Sawyer Anthracycline Cardiotoxicity: From Bench to Bedside J. Clin. Oncol., August 1, 2008; 26(22): 3777 - 3784. [Abstract] [Full Text] [PDF]

				P. Menna, E. Salvatorelli, and G. Minotti Doxorubicin Degradation in Cardiomyocytes J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 408 - 419. [Abstract] [Full Text] [PDF]