QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.103846v1 318/1/424    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Salvatorelli, E. Articles by Minotti, G. Search for Related Content PubMed PubMed Citation Articles by Salvatorelli, E. Articles by Minotti, G.

METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Paclitaxel and Docetaxel Stimulation of Doxorubicinol Formation in the Human Heart: Implications for Cardiotoxicity of Doxorubicin-Taxane Chemotherapies

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

Antitumor therapy with the anthracycline doxorubicin is limited by a dose-related cardiotoxicity that is aggravated by a concomitant administration of the taxane paclitaxel. Previous limited studies with isolated human heart cytosol showed that paclitaxel was able to stimulate an NADPH-dependent reduction of doxorubicin to its toxic secondary alcohol metabolite doxorubicinol. Here we characterized that 0.25 to 2.5 µM paclitaxel caused allosteric effects that increased doxorubicinol formation in human heart cytosol, whereas 5 to 10 µM paclitaxel decreased doxorubicinol formation. The closely related taxane docetaxel caused similar effects. Basal or taxane-stimulated doxorubicinol formation was blunted by 2,7-difluorospirofluorene-9,5'-imidazolidine-2',4'-dione (AL1576), a specific inhibitor of aldehyde reductases. Doxorubicinol was measured also in the cytosol of human myocardial strips incubated in plasma and exposed to doxorubicin in the absence or presence of paclitaxel or docetaxel and their clinical vehicles Cremophor EL or polysorbate 80. Low concentrations of taxanes stimulated doxorubicinol formation, whereas high concentrations decreased it. Doxorubicinol formation reached its maximum on adding plasma with 6 µM paclitaxel or docetaxel; this corresponded to the partitioning of 1.5 to 2.5 µM taxanes in the cytosol of the strips. Taxane-stimulated doxorubicinol formation was not mediated by vehicles, nor was it caused by increased doxorubicin uptake or de novo protein synthesis; however, doxorubicinol formation was blunted by AL1576. These results show that allosteric interactions with cytoplasmic aldehyde reductases enable paclitaxel or docetaxel to stimulate doxorubicinol formation in human heart. This information serves metabolic insights into the risk of cardiotoxicity induced by doxorubicin-taxane therapies.

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]

				E. Salvatorelli, P. Menna, L. Gianni, and G. Minotti Defective Taxane Stimulation of Epirubicinol Formation in the Human Heart: Insight into the Cardiac Tolerability of Epirubicin-Taxane Chemotherapies J. Pharmacol. Exp. Ther., February 1, 2007; 320(2): 790 - 800. [Abstract] [Full Text] [PDF]