Abstract
The clinical utility of the cancer chemotherapeutic agent doxorubicin (DOX) is limited by its cardiotoxicity. Doxorubicinol (DOXol), the major biometabolite of DOX, preferentially accumulates in heart during chronic DOX administration. We now find that DOXol is cardioactive, increasing resting stress in isometrically contracting papillary muscles isolated from rabbit heart. Values in the table were measured after the addition of 50 ug/ml of DOXol or DOX and expressed as the percent (X ± SE) of pretreatment control values.
An increase in resting stress indicates failure of myofibrils to relax and may be related to intracellular calcium ([Ca]i). The table also shows that the greater potency of DOXol, relative to DOX, to increase resting stress correlates with DOXol's greater potency to inhibit, in-vitro, two major determinants of resting [Ca]i, isotopic Na/Ca exchange rate of membrane vesicles enriched in sarcolemma (SL) and Ca pump activity of membrane vesicles enriched in sarcoplasmic reticulum (SR).
Thus we speculate that the abnormalities in myocardial relaxation noted in the chronic cardiotoxicity of DOX may be related to the effects of DOXol on membrane regulation of [Ca]i.
Article PDF
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Boucek, R., Kunkel, E., Graham, T. et al. DOXORUBICINOL, THE METABOLITE OF DOXORUBUCIN, IS MORE CARDIOTOXIC THAN DOXORUBICIN. Pediatr Res 21 (Suppl 4), 187 (1987). https://doi.org/10.1203/00006450-198704010-00127
Issue Date:
DOI: https://doi.org/10.1203/00006450-198704010-00127
This article is cited by
-
Doxorubicin-Induced Cardiotoxicity: An Overview on Pre-clinical Therapeutic Approaches
Cardiovascular Toxicology (2022)