The displacement of iron(III) from its complexes with the anticancer drugspiroxantrone and losoxantrone by the hydrolyzed form of the cardioprotective agent dexrazoxane

Piroxantrone and losoxantrone are new DNA topoisomerase II-targeting anthra pyrazole antitumor agents that display cardiotoxicity both clinically and i n animal models. A study was undertaken to see whether dexrazoxane or its h ydrolysis product ADR-925 could remove iron(III) from its complexes with pi roxantrone or losoxantrone. Their cardiotoxicity may result from the format ion of iron(III) complexes of losoxantrone and piroxantrone. Subsequent red uctive activation of their iron(III) complexes likely results in oxygen-fre e radical-mediated cardiotoxicity. Dexrazoxane is in clinical use as a doxo rubicin cardioprotective agent. Dexrazoxane presumably acts through its hyd rolyzed metal ion binding form ADR-925 by removing iron(III) from its compl ex with doxorubicin, or by scavenging free iron(III), thus preventing oxyge n-free radical-based oxidative damage to the heart tissue. ADR-925 was able to remove iron(III) from its complexes with piroxantrone and losoxantrone, though nut as efficiently or as quickly as it could from its complexes wit h doxorubicin and other anthracyclines. This study provides a basis for uti lizing dexrazoxane for the clinical prevention of anthrapyrazole cardiotoxi city. (C)1999 Elsevier Science Inc. All rights reserved.