Comparative redox activities of anthracyclines by microsomes from P388 cells and rat liver

In comparative tests of the capabilities of various analogs of doxorubicin and daunorubicin to augment oxygen consumption in microsome preparations from P388 mouse leukemia cells and from rat liver cells, we found statistically significant positive correlations between the Km values for microsomes from the two sources for parent compounds and analogs containing morpholinyl, cyanomorpholinyl- or imino-substitutions. Km values ranged from 0.015 to 1.3 mM, or about 90-fold for all analogs tested. Thus, rat liver microsomes are predictive for this characteristic in P388 microsomes. Examinations of the relationships between Km values from either source and ED50 values for cytotoxicity of the compounds against the P-388 cells also showed statistically significant positive correlations. However, the ED50 values encompassed a range from 0.00020 to 0.22 microM, or about 1000-fold. Therefore, additional mechanism(s) of action besides toxic oxygen radical formation must explain the extremely high cytotoxicity of the cyanomorpholinyl anthracyclines compared with their parent drugs.