The effectiveness of amifostine on the prevention of cardiotoxicity of mitoxantrone and idarubicin

THE EFFECTIVENESS OF AMIFOSTINE ON THE PREVENTION OF CARDIOTOXICITY OFMITOXANTRONE AND IDARUBICINIntroduction: Idarubicin (IDA) and mitoxantrone (MITO), used for the treatment of hematological malignanciesand solid tumors, are anthracyline group of antineoplastic drugs. Their most important side effects arecardiotoxicity and myelosupression. It is supposed that lipid peroxidation and oxygen free radicals may play arole on the pathogenesis of anthracyline-induced cardiotoxicity.Aim: To investigate the roles of lipid peroxidation, oxygen free radicals metabolism, and protective enzymeshistopathological and biochemical on the pathogenesis of IDA- and MITO-induced acute cardiotoxicity and theeffectiveness of amifostine (AMI) on the prevention of possible cardiotoxicity in rats.Material and Methods: Animal ethical committee approval and partial support fund from Adnan MenderesUniversity was taken for this study. 156±30g weight 60 male Wistar rats were enrolled and divided t0 10 equalgroups. Serum saline to 1.group, 200 mg/kg AMI to 2.group, 2.5 mg/kg IDA to 3.group, 5 mg/kg IDA to 4.group, 200 mg/kg AMI 2.5 mg/kg IDA 30 min. later to 5.group, 200 mg/kg AMI 5 mg/kg IDA 30 min. later to6.group, 5 mg/kg MITO to 7.group, 5 mg/kg MITO to 8.group, 200 mg/kg AMI 2.5 mg/kg MITO 30 min. laterto 9.group, and 200 mg/kg AMI 5 mg/kg MITO 30 min. later to 5.group were administered. On the 0,1, and 8.days, cardiac enzymes such as creatine phosphokinase-myocardial band (CK-MB) and troponin-T wereexamined from tail veins by using electro-chemiluminescence immunoassay method. Rats were sacrificed on8.day. Superoxide dismutase (SOD), catalase, glutathione peroxidase (Gpx), total glutathione (GSH) andmalondialdehyde (MDA), the indicator of lipid peroxidation, were investigated in the half of the rat heart tissueby using spectrophotometric method. According to appropriate scoring systems, inflammation, degeneration,fibrosis, calcium deposits, and apoptosis were evaluated with light microscope histopathological in another halfof the rat heart tissue. The results were evaluated by using one-way ANOVA and two-paired student?s t tests.Results: The 8.day troponin-T levels in IDA-2.5 group were higher than AMI and control groups (p<0.05).While MDA levels in IDA groups were not different than AMI and control groups (p>0.05), lipid peroxidation inboth MITO groups higher than AMI and control groups (p<0.05 and p<0.001). While MDA levels in bothMITO+AMI groups were not different than AMI and control groups (p>0.05), these levels in MITO-5+AMIgroup were significantly lower than MITO-5 group (p<0.005). Although SOD and catalase levels did not changein MITO groups (p>0.05), catalase (p<0.005 and p<0.001) and total GSH (p<0.001 and p<0.01) levels in MITOgroups were significantly higher than AMI and control groups. In MITO and AMI groups, catalase (p<0.001)and total GSH levels (p<0.001 and p<0.005) were higher than AMI and control groups. In IDA groups, SOD,catalase, Gpx, and total GSH levels were not different than controls (p>0.05). Total GSH levels in MITO groupswere increased by AMI (p<0.001). After histopathological examination, while inflammation scores in bothMITO groups (p<0.001 and p<0.05) were higher than controls, these scores in MITO+AMI groups were lowerthan MITO-2.5 (p<0.05 and p<0.001). While degeneration (Billingham) scores in MITO groups were higherthan controls (p<0.001 and p<0.01), these scores in MITO-5+AMI group were lower than MITO-2.5 group(p<0.005). While fibrosis scores in MITO-2.5 group were higher than control and MITO-5 groups (p<0.005),these scores in MITO-5 +AMI groups were lower than MİTO-2.5 group (p<0.05). Apoptosis scores in MITO-2.5group were higher than MITO-5 (p<0.05) and control groups (p<0.001). These scores in MITO-2.5+AMI groupwere higher than controls (p<0.005). In IDA groups, inflammation and fibrosis did not increase and these scoresdid not change in addition to AMI (p>0.05). Degeneration scores in IDA-5 group were higher than control(p<0.001) and IDA-2.5 groups (p<0.005). The use of alone AMI induced degeneration and inflammation(p<0.001), when compared to controls. Apoptosis scores in IDA-5 group were higher than control (p<0.005) andIDA-2.5 (p<0.05). There was no significant difference between IDA-5+AMI and control groups (p>0.05). Butapoptosis scores in IDA-5+AMI were than IDA-5 group (p<0.05). Calcium deposits were not seen in any rat andAMI did not effect calcium deposits (p>0.05).Conclusions: Lipid peroxidation played a role in mitoxantrone-induced acute cardiotoxicity in rats. Myocardiumincreased catalase and GSH levels to protect from both lipid peroxidation and the harmful effects of oxygen freeradicals. Mitoxantrone caused histopathological inflammation, degeneration, fibrosis, and apoptosis inmyocardium. AMI may prevent mitoxantrone-induced acute cardiotoxicity, decreasing lipid peroxidation andincreasing catalase and GSH levels. However IDA did not effect lipid peroxidation, the preventive enzymes, andGSH with the exception of apoptosis induction. Idarubicin-induced acute cardiotoxicity may result fromdifferent mechanisms. AMI may be partially effect on Idarubicin, increasing GSH levels and decreasingapoptosis.Key words: Amifostine, idarubicin, cardiotoxicity, mitoxantrone, rat