3′-Deamino-3′-(2-methoxy-4-morpholinyl)-doxorubicin (FCE 23762): A new anthracycline derivative with enhanced cytotoxicity and reduced cardiotoxicity

Abstract

The purpose of this study was to examine the cytotoxicity and cardiotoxicity of the new doxorubicin derivative, 3′-deamino-3′-(2-methoxy-4-morpholinyl)-doxorubicin (FCE 23762). The concentration of FCE 23762 that resulted in a 50% reduction in colony formation of DU 145, COLO 320DM, A549 and A2780 human cancer cell lines ranged from 1.1 and 3.2 nmol/l and was 3–9 times as low as doxorubicin. In the isolated perfused rat hearts, doxorubicin 10 −5 mol/l induced a significant prolongation of SαT segment and Q-F max interval, and reduction in dF dt max and coronary flow while only FCE 23762 10 −5 mol/l induced a widening of QRS complex. Anaesthetised rats given a single intravenous (i.v.) dose of doxorubicin 10 mg/kg showed significant changes in both ECG (SαT segment and QRS complex enlargement) and haemodynamic parameters (increase in mean arterial blood pressure and reduction in systemic arterial dP dt max ), while animals given FCE 23762 (0.1 and 0.3 mg/kg) had a significant increase in QRS complex duration after the highest dose. In the chronic cardiotoxicity study animals receiving FCE 23762 (0.03 mg/kg i.v. once a week for 3 weeks) did not show any significant alteration of ECG and minor changes of cardiac histological picture; by contrast doxorubicin (3 mg/kg i.v. once a week for 3 weeks) induced a severe cardiomyopathy, characterised by progressive widening of SαT segment, increase in T wave and histological damage consisting of vacuolations and loss of myofibrils. These results indicate that FCE 23762 is more active in vitro than doxorubicin and markedly less cardiotoxic in vivo at the doses used in the present study.