Cardiac myocytes isolated from 2 day old rats were cultured in Primaria flasks for 8 days. The were incubated with various analogs of daunomycin and adriamycin at clinically relevant micromolar concentrations for up to 96 hours. The cell death was monitored using a number of parameters such as loss of cell ATP, depletion of cell GSH, leakage of adenine nucleotides and cytoplasmic enzyme such as lactic acid dehydrogenase. In general the cells lost ATP and GSH before the leakage of enzyme and adenine nucleotides. Modification of adriamycin and daunomycin molecule markedly increased or decreased the toxicity depending on the modification. The most toxic compound was found to be cyano morpholino analog of adriamycin. These analogs were also tested for their antitumor activities against mouse leukemia L1210 cells. These drugs also depleted cell ATP and GSH before cell death. However, their effect on the growth of the L1210 cells were somewhat independent of their effects on ATP and GSH. In general an increase in antitumor effects induced by certain chemical modifications also increased cardiotoxicity of anthracycline analogs. However certain modification in the structure increased the cardiotoxicity without an increase in their antitumor effect and vice versa. It can be concluded from these studies that the mechanism of cell death in cardiac myocytes and tumor cell may involve the effect on ATP synthesis while the effect of anthracycline on cell growth may involve other factors such as intercalation with DNA and inhibition of DNA synthesis.
