Reduced cardiotoxicity and increased cytotoxicity in a novel anthracycline analogue, 4′-amino-3′-hydroxy-doxorubicin

Abstract

The acute and chronic cardiotoxicity and cytotoxicity of the novel doxorubicin (DXR) derivative 4'-amino-3'-hydroxy-DXR were compared with those of 4'-deoxy-DXR and DXR. In the acute cardiotoxicity study, the ECG and hemodynamic changes recorded in anesthetized rats that had been treated i.v. with 10 mg/kg 4'-amino-3'-hydroxy-DXR or 8.6 mg/kg 4'-deoxy-DXR were significantly less severe than those caused by 13 mg/kg DXR. In the chronic cardiotoxicity study, rats received 3 weekly i.v. injections of 3 mg/kg DXR, 3 mg/kg 4'-amino-3'-hydroxy-DXR, or 2 mg/kg 4'-deoxy-DXR during the first 14 days of the study and were observed for an additional 35-day period. DXR induced severe cardiomyopathy that was characterized by ECG changes in vivo (S alpha T-segment widening and T-wave flattening) and by impairment of the contractile responses (Fmax, +/- dF/dtmax) to adrenaline of hearts isolated from treated animals. 4'-Deoxy-DXR caused a progressive enlargement of the S alpha T segment in vivo and a significant impairment of the -dF/dtmax value in vitro, which were less severe than those produced by DXR. The least cardiotoxic drug was 4'-amino-3'-hydroxy-DXR, which induced minor ECG changes without causing significant alterations in the contractile responses of isolated hearts to adrenaline. On the basis of the drug concentration required to inhibit 50% of the colony formation (IC50) of cell lines in vitro, 4'-amino-3'-hydroxy-DXR was less active than 4'-deoxy-DXR but at least twice as active as DXR against human cancer and murine transformed cell lines. These data indicate that 4'-amino-3'-hydroxy-DXR is significantly less cardiotoxic and more cytotoxic than DXR.

Protective effect ofSpirulina against doxorubicin-induced cardiotoxicity

“…In mice treated with Spirulina, these DOX-induced histological changes were minimal, suggesting protection from cellular damage by DOX. The changes demonstrated microscopically in the DOX-treated group were similar to those observed by us and others (Zbinden and Brandle, 1975;Danesi et al, 1992;Naidu et al, 2002). The reversal of DOX-induced ultrastructural changes and the restoration of antioxidant status by Spirulina demonstrated that Spirulina could ameliorate the DOX-induced myocardial damage.…”

The role of nitric oxide in anthracycline toxicity and prospects for pharmacologic prevention of cardiac damage

“…The reduction in NO levels may be enhanced by the production of superoxide by redox cycling, because superoxide is able to quench NO to form ONOO - (38). Owing to the importance of NO as a key regulator of vascular tone and an important mediator in the myocardial contractile response, the resulting acute change in NO homeostasis may account at least in part for the early electrocardiographic changes that occur upon administration of anthracyclines in rats (39) and mice (30).…”