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.
Pinna
A
A
Istituto di Farmacologia Medicà, Universita di Pisa, Italy.
Agen
C
C
Di Paolo
A
A
Innocenti
F
F
Nardini
D
D
Danesi
R
R
Del Tacca
M
M
D000704:Analysis of Variance; D000818:Animals; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000633:toxicity; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects*; D006331:Heart Diseases / Q000139:chemically induced; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured / Q000187:drug effects
C066998:methoxy-morpholinyl-doxorubicin; C053044:4'-deoxy-4'-iododoxorubicin; D004317:Doxorubicin