Comparison of cytotoxicity in heart cells and tumor cells exposed to DNA intercalating agents in vitro.
A new approach to antitumor analog selection was evaluated using in vitro cytotoxicity assays in tumor cells and heart cells. Eight anthracycline antibiotics and five non-anthracycline DNA intercalating agents were separately exposed to human 8226 myeloma cells and neonatal rat heart myocytes in vitro. Survival was measured after six days of culture by the MTT dye method for tumor cells and by ATP content for heart cells. Inhibitory drug concentrations in 50% of cells (IC50) were determined from log-linear dose-response curves for each agent. The IC50 values in the tumor cells ranged from 0.002 micrograms/ml for idarubicin to 3.5 micrograms/ml for the primary metabolite of doxorubicin, doxorubicinol. In contrast, IC50 values for anthracyclines in rat heart cells averaged approximately 357-fold higher than in the tumor cells. The heart cell/tumor IC50 ratio was 114.4 for the parent anthracycline doxorubicin. Compounds with poor cytotoxic selectivity for tumor cells included doxorubicinol, amonafide, amsacrine and bisantrene. Compounds with reduced cardiotoxicity included the anthracyclines daunorubicin (IC50 ratio of 550), esorubicin (IC50 ratio of 1500) and the anthracene derivative mitoxantrone (IC50 ratio of 500). These results show that simultaneous comparisons of cytotoxicity in heart cells and tumor cells can identify agents such as daunorubicin and mitoxantrone which are known to produce less cardiac toxicity in vivo. With further testing, this methodology may be applicable to preclinical screening programs to select active DNA intercalating agents with low cardiotoxic potential.
Dorr
R T
RT
University of Arizona, Pharmacology Department, Tucson.
Shipp
N G
NG
Lee
K M
KM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D003864:Depression, Chemical; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007364:Intercalating Agents / Q000009:adverse effects / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007364:Intercalating Agents; D000255:Adenosine Triphosphate; D004247:DNA; D007770:L-Lactate Dehydrogenase