COMPARISON OF DIFFERENT IRON CHELATORS AS PROTECTIVE AGENTS AGAINST ACUTE DOXORUBICIN-INDUCED CARDIOTOXICITY

Doxorubicin (Dox) is a widely used antineoplastic agent. Irreversible cardiomyopathy is a serious and dose-limiting side effect after chroni c administration. The iron chelating bispiperazinedione ICRF-187 is cu rrently the only drug which affords protection against Dox-induced car diotoxicity. To compare the protective value of structurally unrelated iron chelators, isolated mice atria were exposed to Dox (30 mu M) and either the hydroxamate desferrioxamine (DFO, 200 and 500 mu M), EDTA (200 mu M) or the hydroxypyridones CP44 (200 mu M), CP51 (200 mu M), a nd CP93 (200 mu M) and ICRF-187 (200 and 500 mu M). The nitroxide TEMP O (5 mM) lacks iron chelating properties but was used to prevent redox cycling or iron and scavenge superoxide. All iron chelators, except E DTA, CP93 and CP44, were modestly protective against a Dox-induced dec rease in contractile force. As a single agent the hydroxypyridones dec reased atrial contractile force. At a concentration of 200 mu M, DFO w as the most effective protector of the chelators tested. However, this effect disappeared when a concentration of 500 mu M was used. This in contrast to ICRF-187 for which a concentration-dependent inhibition o f Dox-induced decrease in contractile force was observed. TEMPO exerte d a biphasic response consisting of a two-fold increase in contractile force, followed by a decrease in force and irregular contractions. In this model TEMPO lacked any perspective as a cardioprotectant. We con clude that at 200 mu M, DFO was the most effective agent to afford pro tection against Dox-mediated atrial malfunction. However, at 500 mu M, DFO was not effective whereas ICRF-187 afforded partial protection. H ydroxipyridones were found to be of limited value because of a negativ e inotropic effect on the isolated atria.