Is Amifostine Effective on the Protection of Mitoxantrone-Induced Acute Cardiotoxicity? A Biochemical and Histopathological Experimental Study.

Background: Mitoxantrone (MTX), an anthracenedione derivate, is used in the treatment of several malignancies. One of the most important adverse effects is dose-dependent cardiotoxicty. Myocardial adrenergic imbalance, oxygen free radicals, tumor necrosis factor-alpha, interleukin-2, and increased intracellular calcium may play role in the development of anthracycline-induced cardiotoxicity.

Aim: In this study, the roles of lipid peroxidation, oxygen free radicals and protective enzymes, and the protective effect of amifostine (AMI) were evaluated using biochemical and histopathological methods on mitoxantrone-induced acute cardiotoxicity in rat heart.

Materials and method: This study was performed on 36 male Wistar rats. Rats were divided to equal 6 groups:

• Control group was received as serum saline 10 ml/kg, intraperitoneally (IP),

• AMI group 200 mg/kg IP,

• MTX 2.5 mg/kg group IP,

• MTX 5 mg/kg group IP,

• MTX 2.5 mg/kg+AMI 200 mg/kg group IP, and

• MTX 5 mg/kg+AMI 200 mg/kg IP.

AMI was performed before 30 min. MTX in last two groups. Creatine kinase-myocardial band (CK-MB) and troponin-T were analyzed at pre-study, 1^st, and 7^th days. Rats were killed after 7 days. Malondialdehyde (MDA), catalase, superoxide dismutase (SOD), total glutathione (GSH), and glutathione peroxidase (Gpx) were analyzed with spectrophotometric method in rat heart. Fibrosis, inflammation, degeneration, apoptosis, and calcium deposits in myocardium were evaluated with pathological examination and scoring system. This study was approved by university animal ethic committee and supported by University.

Results: CK-MB and troponin-T levels were not different between six groups and three assays (p>0.05). MDA levels in MTX were higher than those of control and AMI goups (p<0.05, p<0.001, respectively). Moreover MDA levels in AMI+MTX groups were not different compared to control and AMI groups (p>0.05). SOD levels in MTX 5+AMI group was higher than controls (p<0.005). Catalase levels in both MTX and MTX+AMI groups significantly increased than those of control and AMI goups (p<0.001, p<0.05, respectively). Total GSH levels in MTX and MTX+ AMI groups higher than those of control and AMI groups (p<0.001, p<0.005, respectively). Gpx levels in MTX 5+AMI were lower compared to MTX 2.5 group (p<0.05). Calcium deposits were not detected in any rat. Myocardial fibrosis score in MTX 2.5 groups was higher than those of control (p<0.001), AMI (p<0.05), MTX 5 (p<0.005), and MTX 5+AMI (p<0.005) groups. Billingham score for myocardial degeneration in all groups was higher than controls (p<0.001). Apopitosis score in MTX 2.5 group increased compared to control, AMI (p<0.001) and MTX 5 (p<0.05) groups. Inflammation score in AMI, MTX 2.5 and 5 groups was higher than controls (p<0.001). Whereas inflammation in MTX+AMI groups decreased than those of MTX 2.5 group (p<0.05,p<0.001, respectively).

Conclusion: While MTX causes inflammation, fibrosis, degeneration, and apopitosis in rat heart, it induces lipid peroxidation. Moreover AMI may protect myocardium from MTX-induced lipid peroxidation and histopathological damage.