Structural requirements for anthracycline-induced cardiotoxicity and antitumor effects.
By employing rat cardiac myocytes in culture and mouse L-1210 leukemia cells, we have compared different anthracycline analogs with respect to their ability to kill cardiac myocytes and tumor cells. Anthracyclines induced a decrease in cellular ATP and glutathione from both cardiac myocytes and L-1210 cells in a time- and concentration-dependent fashion. Moreover, the decrease in ATP in cardiac myocytes was followed by release of the cytoplasmic enzyme lactic acid dehydrogenase and of adenine nucleotides after anthracycline treatment. At very low concentrations of anthracyclines, at which ATP and glutathione were not affected, the drugs induced complete cessation of the growth of L-1210 cells. Some structural alterations in the anthracycline molecule resulted in parallel changes in antitumor activity and in cardiotoxicity. But other structural alterations resulted in dissimilar changes in antitumor activity and cardiotoxicity. Although the results indicate that the structural requirements for inducing cardiotoxicity and antitumor activity may be different, they also indicate that the mechanisms by which anthracycline causes cell death in tumor cells and cardiac myocytes may be the same.
Section on Drug Tissue Interaction, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892.
Y
Y
Singh
L
L
Ulrich
D
D
Katz
P
P
Bowen
G
G
Krishna
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D006321:Heart / Q000187:drug effects*; D007928:Lethal Dose 50; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D004317:Doxorubicin; D003630:Daunorubicin