The use of serum levels of cardiac troponin T to compare the protective activity of dexrazoxane against doxorubicin and mitoxantrone-induced cardiotoxicity

Purpose: To compare the protective effect of dexrazoxane (DRZ) against card iotoxicity induced by doxorubicin (DXR) and mitoxantrone (MTX). Methods: Ad ult male spontaneously hypertensive rats (SHR) were treated with 1 mg/kg DX R (i.v.) or 0.5 mg/kg MTX (i.v.), either alone or 30 min after 25 mg/kg DRZ (i.p.) weekly for up to 12 weeks. Animals treated with DXR alone either di ed (n = 2) or were killed (n = 3) at a cumulative dose of 10 mg/kg. The sev erity of cardiac lesions (cytoplasmic vacuolization and myofibrillar loss) were graded semiquantitatively by light microscopy on a scale of 0 to 3. Re sults: Cardiac lesions were observed in all SHR given DXR or MTX alone, and were attenuated in those given DRZ prior to either DXR (mean lesion scores 2.7 vs 1.5; P < 0.05) or MTX (mean lesion scores 2.0 vs 1.25; P <0.05). Ca rdioprotection was also demonstrated by monitoring serum levels of cardiac troponin T (cTnT), which were elevated in all animals receiving DXR or MTX alone. These elevations were attenuated in SHR given the combination of DXR and DRZ (mean values 0.79 ng/ml vs 0.24 ng/ml; P < 0.05) and MTX and DRZ ( mean values 0.19 ng/ml vs 0.04 ng/ml; P < 0.05). Biochemical studies have s hown that both DXR and MTX form potentially cardiotoxic complexes with iron . ADR-925 (the hydrolysis product of DRZ) and other chelators (EDTA., dieth ylenetriaminepentaacetic acid and desferrioxamine) removed Fe(III) from its complex with MTX or DXR. Conclusions: The present study showed that DRZ si gnificantly attenuates the cardiotoxicity induced by DXR and MTX, and that this protective activity can be assessed by morphological evaluation of car diac tissues and by monitoring the concentrations of cTnT in serum.