Selective inhibition of cardiac cyclic nucleotide phosphodiesterases by doxorubicin and daunorubicin.
Doxorubicin and daunorubicin, the anthracycline antitumor agents, were evaluated for their in vitro and in vivo effect on phosphodiesterase (PDE) activity in mouse tissues. Doxorubicin at a concentration of 10(-4)M inhibited cardiac c-AMP (adenosine 3',5', monophosphate) PDE activity 50% of the control whereas in lungs and spleen, the activity was inhibited only 20%. On the contrary no effect was seen in kidney and liver. In addition, cardiac c-GMP (guanosine 3',5' monophosphate) PDE appeared less sensitive to doxorubicin than c-AMP PDE though inhibition in heart was more pronounced than in any other tissue. It appears that daunorubicin inhibits c-AMP PDE activity in heart markedly less than doxorubicin. Kinetic studies indicate that both inhibitions of c-AMP and c-GMP PDE by doxorubicin were non-competitive with substrate. Intravenous administration of 20 and 30 mg/kg of free doxorubicin to CDF1 mice resulted in 33 and 39% decreases in cardiac c-AMP PDE activity respectively by 72 hrs. In contrast, similar intravenous injections of same doses of doxorubicin entrapped in cardiolipin liposomes had no effect on c-AMP PDE activity in any tissues. These studies demonstrate the relative selectivity of the cardiac cyclic nucleotide PDE inhibitory effect of doxorubicin suggesting that this inhibition might be one aspect of the mechanism of anthracycline-induced cardiotoxicity.
Law
J
J
Fumagalli
A
A
Schein
P S
PS
Rahman
A
A
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D003630:Daunorubicin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000201:enzymology; D051379:Mice; D009206:Myocardium / Q000201:enzymology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D013154:Spleen / Q000201:enzymology
D010726:Phosphodiesterase Inhibitors; D004317:Doxorubicin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D003630:Daunorubicin