Key result
Dexrazoxane pretreatment fails to alter anthracycline growth inhibition, suggesting iron-mediated ROS is not the mechanism.
The study demonstrates that anthracyclines do not inhibit cell growth through iron-mediated reactive oxygen species, separating their antitumor mechanism from their cardiotoxic mechanism.
Supports dissociation of antitumor and cardiotoxic pathways; hypothesis-generating pending clinical validation.
The use of the anthracycline anticancer drugs doxorubicin and daunorubicin is limited by what is thought to be an iron-based oxygen radical-derived dose-dependent cardiotoxicity. The anthracyclines are also DNA topoisomerase (Topo) II poisons. It is not known if iron-mediated formation of reactive oxygen species (ROS) by the anthracyclines or their Topo II inhibitory effects are responsible for their cell growth-inhibitory effects. Experiments to test these two alternatives were carried out using a CHO-derived cell line (DZR) that was highly resistant to dexrazoxane through a Thr48IIe mutation in Topo IIalpha. The clinically used cardioprotective agent dexrazoxane likely exerts its cardioprotective effects through the chelating ability of its hydrolysis product ADR-925, an analog of EDTA. Dexrazoxane is also a cell growth inhibitor that acts through its ability to inhibit the catalytic activity of Topo II. Thus, the DZR cell line allowed us to examine the cell growth-inhibitory effects of doxorubicin and daunorubicin in the presence of dexrazoxane without the confounding effect of dexrazoxane inhibiting cell growth. The growth-inhibitory effects of neither doxorubicin nor daunorubicin were affected by pretreating DZR cells with dexrazoxane. In contrast, under similar conditions, dexrazoxane strongly protected rat cardiac myocytes from doxorubicin-induced lactate dehydrogenase release. In conclusion, the anthracyclines do not inhibit the growth of DZR cells through the generation of iron-mediated formation of ROS.
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Wu et al. (2004) studied Anthracycline-induced cell growth inhibition and cardiotoxicity. Doxorubicin and daunorubicin with or without dexrazoxane pretreatment vs. Control conditions without dexrazoxane pretreatment was evaluated on Cell growth inhibition and lactate dehydrogenase release. Pretreatment with dexrazoxane did not affect the growth-inhibitory effects of doxorubicin or daunorubicin in DZR cells, indicating anthracyclines do not inhibit cell growth via iron-mediated ROS.