Iron chelators have been studied as protectors against doxorubicin-induced cardiotoxicity. The bispiperazinedione ICRF 187 has been studied extensively. ICRF 187 is also known as dexrazoxane and is the more water soluble (+)enantiomorph of the racemic mixture ICRF-159, which was originally developed as a conventional antineoplastic agent [
2]. In phase I trials using a variety of schedules in both adults and children, dose-limiting toxicities on most schedules were myelosuppression, except in children, in whom the major dose-limiting toxicity was hepatotoxicity [
3]. In addition, research conducted at the same time as the initial phase I studies showed that the divalent chelating properties of ICRF-159 and 187 could protect animals from the cardiotoxicity induced by anthracyclines [
4,
5]. This further corroborated the catalytic toxic role of iron ions in the doxorubicin-induced cardiotoxicity. There are several disadvantages associated with the use of ICRF-187. ICRF-187 exerts a dose-dependent myelosuppression, which may limit its addition to chemotherapy. Moreover, controversy exists as to whether ICRF-187 decreases the antitumour activity of doxorubicin. ICRF-187 is a prodrug which requires hydrolysis to achieve the active form. Finally, ICRF-198, the hydrolyzed form of ICRF-187 is an EDTA-like chelator. This implies that because of stoichiometrical restrictions the drug lacks the ability to occupy all six coordination sites of iron. Consequently, iron remains catalytically active to generate oxygen radicals. Besides iron chelators as ICRF-187 and for example deferoxamine, many other compounds have been evaluated for their potential to reduce doxorubicin-induced cardiotoxicity, based on a perceived ability to modulate some of the biochemical alterations that accompany doxorubicin administration. The list of compounds includes adenosine, anti-histamine agents (both H
1 and H
2 blockers), beta-adrenoceptor antagonists, amrinone, milrinone, fructose-1,6-diphosphate, inosine, ibuprofen, dextran, methylprednisone, salts of bismuth, zinc and calcium, tetracycline antibiotics and a number of iron chelators as deferoxamine, ICRF-187. In addition, various antioxidants have been applied as vitamin E, curcumin, lipoic acid and venoruton.
In view of the suggested molecular mechanism involved in doxorubicin-induced cardiotoxicity we searched for protectors which combine iron-chelating and oxygen radical scavenging properties. Moreover, the novel protector should not interfere with the cytostatic activity of doxorubicin.