Dissociation between in vitro cytotoxicity and in vivo cardiotoxicity of two new anthracyclines: 3'-deamino-3'-(2-methoxy-4-morpholinyl)doxorubicin and 4'-deoxy-4'-iodo-doxorubicin

The purpose of this study was to examine the cytotoxicity and cardiotoxicity of new doxorubicin (DXR) derivatives, 3'-deamino-3'-(2-methoxy-4- morpholinyl)DXR (MRA-MT), and 4'-deoxy-4'-iodo-doxorubicin (IDXR), comparing them to doxorubicin (DXR). Both anthracycline derivatives were approximately 1.5- to 9-fold more active than DXR in inhibiting the colony-formation ability of DU145, HOS, and A2780 human cancer cell lines. Anesthetized rats given a single intravenous (i.v.) dose of DXR 10 mg/kg showed significant changes in both ECG (S alpha T segment and QRS complex widening) and hemodynamic parameters (impairment in systemic arterial dP/dtmax systolic and diastolic blood pressure), whereas animals that received MRA-MT (0.1 and 0.3 mg/kg) had no significant signs of acute cardiotoxicity. In this case the animals treated with IDXR 1.2 mg/kg showed alterations in the ECG as the animals treated with DXR. In the chronic cardiotoxicity study, some animals received MRA-MT (0.03 mg/kg i.v. once a week for 3 weeks) and others IDXR (4 mg/kg once a week for 3 weeks). They did not show any alteration in ECG and cardiac histological picture. By contrast, DXR (3 mg/kg i.v. once a week for 3 weeks) induced a severe cardiomyopathy, characterized by progressive widening of S alpha T segment, increase in T wave, and histological damage consisting of vacuolations and loss of myofibrils. These results suggest that MRA-MT and IDXR are more active in vitro and markedly less cardiotoxic in vivo than DXR.

The purpose of this study was to examine the cytotoxicity and cardiotoxicity of new doxorubicin (DXR) derivatives, 3'-deamino-3'-(2- methoxy-4-morpholinyl)DXR (MRA-MT), and 4'-deoxy-4'-iodo-doxorubicin (IDXR), comparing them to doxorubicin (DXR). Both anthracycline derivatives were ~1.5- to 9-fold more active than DXR in inhibiting the colony-formation ability of DU145, HOS, and A2780 human cancer cell lines. Anesthetized rats given a single intravenous (i.v.) dose of DXR 10 mg/kg showed significant changes in both ECG (SαT segment and QRS complex widening) and hemodynamic parameters (impairment in systemic arterial dP/dt(max) systolic and diastolic blood pressure), whereas animals that received MRA-MT (0.1 and 0.3 mg/kg) had no significant signs of acute cardiotoxicity. In this case the animals treated with IDXR 1.2 mg/kg showed alterations in the ECG as the animals treated with DXR. In the chronic cardiotoxicity study, some animals received MRA-MT (0.03 mg/kg i.v. once a week for 3 weeks) and others IDXR (4 mg/kg once a week for 3 weeks). They did not show any alteration in ECG and cardiac histological picture. By contrast, DXR (3 mg/kg i.v. once a week for 3 weeks) induced a severe cardiomyopathy, characterized by progressive widening of SαT segment, increase in T wave, and histological damage consisting of vacuolations and loss of myofibrils. These results suggest that MRA-MT and IDXR are more active in vitro and markedly less cardiotoxic in vivo than DXR.