The use of serum levels of cardiac troponin T to compare the protective activity of dexrazoxane against doxorubicin- and mitoxantrone-induced cardiotoxicity.
OBJECTIVE
To compare the protective effect of dexrazoxane (DRZ) against cardiotoxicity induced by doxorubicin (DXR) and mitoxantrone (MTX).


METHODS
Adult male spontaneously hypertensive rats (SHR) were treated with 1 mg/kg DXR (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 died (n = 2) or were killed (n = 3) at a cumulative dose of 10 mg/kg. The severity of cardiac lesions (cytoplasmic vacuolization and myofibrillar loss) were graded semiquantitatively by light microscopy on a scale of 0 to 3.


RESULTS
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). Cardioprotection 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 shown that both DXR and MTX form potentially cardiotoxic complexes with iron. ADR-925 (the hydrolysis product of DRZ) and other chelators (EDTA, diethylenetriaminepentaacetic acid and desferrioxamine) removed Fe(III) from its complex with MTX or DXR.


CONCLUSIONS
The present study showed that DRZ significantly attenuates the cardiotoxicity induced by DXR and MTX, and that this protective activity can be assessed by morphological evaluation of cardiac tissues and by monitoring the concentrations of cTnT in serum.
Herman
E H
EH
Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, Food and Drug Administration, Laurel, MD 20708, USA. hermaneu@cder.fda.gov
Zhang
J
J
Rifai
N
N
Lipshultz
S E
SE
Hasinoff
B B
BB
Chadwick
D P
DP
Knapton
A
A
Chai
J
J
Ferrans
V J
VJ
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D015415:Biomarkers / Q000032:analysis; D002317:Cardiovascular Agents / Q000494:pharmacology*; D004317:Doxorubicin / Q000009:adverse effects*; D006321:Heart / Q000187:drug effects; D007262:Infusions, Intravenous; D008297:Male; D008942:Mitoxantrone / Q000009:adverse effects*; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D011918:Rats, Inbred SHR; D011929:Razoxane / Q000494:pharmacology*; D020107:Troponin T / Q000097:blood*
D000970:Antineoplastic Agents; D015415:Biomarkers; D002317:Cardiovascular Agents; D020107:Troponin T; D011929:Razoxane; D004317:Doxorubicin; D008942:Mitoxantrone