Document Detail


Defective taxane stimulation of epirubicinol formation in the human heart: insight into the cardiac tolerability of epirubicin-taxane chemotherapies.
MedLine Citation:
PMID:  17135345     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Emanuela Salvatorelli; Pierantonio Menna; Luca Gianni; Giorgio Minotti
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-11-29
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  320     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-01-22     Completed Date:  2007-03-13     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  790-800     Citation Subset:  IM    
Affiliation:
Department of Drug Sciences and Center of Excellence on Aging, G. d'Annunzio University School of Medicine, Via dei Vestini, 66013 Chieti, Italy.
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MeSH Terms
Descriptor/Qualifier:
Aged
Antineoplastic Agents / toxicity*
Cytosol / metabolism
Doxorubicin / analogs & derivatives*,  metabolism
Epirubicin / metabolism,  toxicity*
Female
Fluorenes / pharmacology
Heart / drug effects*
Humans
Hydantoins / pharmacology
Hydrogen Peroxide / metabolism
Male
Middle Aged
Myocardium / metabolism*
Paclitaxel / toxicity*
Reactive Oxygen Species
Taxoids / toxicity*
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Fluorenes; 0/Hydantoins; 0/Reactive Oxygen Species; 0/Taxoids; 15H5577CQD/docetaxel; 23214-92-8/Doxorubicin; 33069-62-4/Paclitaxel; 56420-45-2/Epirubicin; 7722-84-1/Hydrogen Peroxide; 89391-50-4/imirestat; 89780-72-3/4'-deoxydoxorubicinol

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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