Anthracycline antibiotics are among the most effective and widely used antineoplastic drugs. Their usefulness is limited by a cumulative dose-related cardiotoxicity, whose precise mechanisms are not clear as yet. The principal role is possibly exerted by free oxygen radicals generated by “redox-cycling“ of anthracycline molecule and/or by the formation of anthracycline-ferric ion complexes. The iron catalyzes the hydroxyl radical production via Haber-Weiss reaction. The selective toxicity of ANT against cardiomyocytes results from high accumulation of ANT in cardiac tissue, appreciable production of oxygen radicals by mitochondria and relatively poor antioxidant defense systems. Other additional mechanisms of the anthracycline cardiotoxicity have been proposed - calcium overload, histamine release and impairment in autonomic regulation of heart function. The currently used methods for an early identification of anthracycline cardiotoxicity comprise ECG measurement, biochemical markers, functional measurement and morphologic examination. Among a plenty of studied cardioprotective agents only dexrazoxane (ICRF-187) has been approved for clinical use. Its protective effect likely consists in intracellular chelating of iron. However, in high doses dexrazoxane itself may cause myelotoxicity. This fact encourages investigation of new cardioprotectants with lower toxicity. Orally active iron chelators and flavonoids attract more attention. Modification of dosage schedule and synthesis of new anthracycline analogues may represent alternative approaches to mitigate anthracycline cardiotoxicity while preserving antitumour activity.

Background: Cardiac toxicity associated with chronic administration of anthracycline (ANT) antibiotics represents a serious complication of their use in anticancer chemotherapy, but can also serve as a useful experimental model of cardiomyopathy and congestive heart failure. Aims: In this study, a model of chronic ANT cardiotoxicity induced by repeated i.v. daunorubicin (DAU) administration to rabbits was tested. Methods: Three groups of animals were used: (1) control group-10 animals received i.v. saline; (2) 11 animals received DAU (3 mgykg, i.v.); (3) 5 animals received the model cardioprotective agent dexrazoxane (DEX, 60 mgykg, i.p.), 30 min prior to DAU. All substances were administered once weekly, for 10 weeks. The DAU-induced heart damage and protective action of DEX were determined and quantitated with the use of histopathology, invasive haemodynamic measurements (e.g. left ventricular pressure changes-dPydt , dPydt ), non-invasive systolic function examinations (left max min ventricular ejection fraction, PEPyLVET index) and biochemical analysis of cardiac troponin T plasma concentrations. Results: All the employed methods showed unambiguously pronounced heart impairment in the DAU group, with the development of both systolic and diastolic heart failure, as well as significant reduction of DAU-cardiotoxicity in DEX-pretreated animals. Other toxicities were acceptable. Conclusion: The presented model has been approved to be consistent and reliable and it can serve as a basis for future determinations and comparisons of chronic cardiotoxic effects of various drugs, as well as for the evaluation of potential cardioprotectants.

This study compares the chronic toxicity of two anthracyclines–daunorubicin and doxorubicin, commonly used for induction of anthracycline cardiomyopathy in the rabbit model. Such a comparative study has not been published until now. Both drugs were administered intravenously to male Chinchilla rabbits in doses at 3 mg/ kg (50 mg/m2) once weekly for 10 weeks. Selected biochemical, haematological and cardiovascular parameters and body weights were regularly monitored; additionally, a histological evaluation of heart, kidney and liver was performed at the end of the experiment. In the daunorubicin group, there were marked signs of the progressive development of heart failure, like the significant increases of the pre-ejection period/left ventricular ejection time index values (up to 134%)–and histological changes within the myocardium were also observed. On the other hand, the 10-week doxorubicin administration did not cause these changes that are typical for heart injury. Haematotoxicity, manifested particularly by aplastic anaemia, was apparent in both the experimental groups. Significant body weight loss (by 45.2%) and high premature mortality (100% versus 36.4%) reflected a greater general toxicity, especially nephrotoxicity of doxorubicin in comparison with daunorubicin. Further studies are necessary to find a possible explanation for these findings.

No abstract

Salicylaldehyde Isonicotinoyl Hydrazone (SIH) – a Pyridoxal Isonicotinoyl Hydrazone (PIH) analogue – is an effective iron chelator with antioxidant and antimalarial effects, as documented in numerous in vitro studies. However, no toxicological data obtained from in vivo studies have been made available yet. In this study, the potential toxic effects of repeated administration of SIH (50 mg/kg, once weekly, 10 weeks, i.p.), partially dissolved in a 10 % Cremophor solution, on various biochemical, haematological, and cardiovascular parameters and on morphology of selected tissues were investigated in rabbits. The obtained values were compared with data from the control (saline, 1 ml/kg, i.v.) and the Cremophor (10 % Cremophor solution, 2 ml/kg, i.p.) groups. In this study, SIH did not induced marked signs of toxicity: No premature deaths occurred, the body weight increase was comparable with the control and Cremophor groups. Only few and mild changes in some biochemical and haematological parameters could be determined, most of them were noticed also in the control or Cremophor groups. The morphological changes in the kidney were mild and did not manifest in the biochemical examination. The cardiac function was also not affected markedly – the values of left ventricular ejection fraction and systolic time interval did not differ from the values of control group. Only an increased left ventricular contractility (dP/dtmax) was noticed in the SIH group at the end of the experiment as compared to the controls (13354±1191 vs. 9339±647 mmHg/s, resp.). These results seem to be promising from the standpoint of possible clinical use of SIH.