3'-Deamino-3'-(2-methoxy-4-morpholinyl)-doxorubicin (FCE 23762): a new anthracycline derivative with enhanced cytotoxicity and reduced cardiotoxicity.
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 (FEC 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 S alpha T segment and Q-Fmax interval, and reduction in dF/dtmax 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 (S alpha T segment and QRS complex enlargement) and haemodynamic parameters (increase in mean arterial blood pressure and reduction in systemic arterial dP/dtmax), 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 S alpha T 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.
Danesi
R
R
School of University Studies and Doctoral Research S. Anna, Pisa, Italy.
Agen
C
C
Grandi
M
M
Nardini
V
V
Bevilacqua
G
G
Del Tacca
M
M
D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D014410:Tumor Stem Cell Assay
C066998:methoxy-morpholinyl-doxorubicin; D004317:Doxorubicin