Reduced cardiotoxicity and increased cytotoxicity in a novel anthracycline analogue, 4'-amino-3'-hydroxy-doxorubicin.
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.
Danesi
R
R
Institute of Medical Pharmacology, University of Pisa, Italy.
Bernardini
N
N
Agen
C
C
Costa
M
M
Zaccaro
L
L
Pieracci
D
D
Malvaldi
G
G
Del Tacca
M
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000633:toxicity*; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; C073151:4'-amino-3'-hydroxydoxorubicin; D004317:Doxorubicin; C030851:esorubicin