Molecular pharmacological differences between carminomycin and its analog, carminomycin-11-methyl ether, and adriamycin.

The effects of carminomycin and its 11-methyl ether analog were characterized and compared with those of Adriamycin in several systems both in vivo and in vitro. When comparing maximum effective doses, carminomycin was found to be ap proximately I 0to 20-fold more potent in vivo than was Adria mycin against mouse Li 210 leukemia, and the latter agent was approximately equipotent with carminomycin-i 1-methyl ether. Similarly, 50% inhibitory concentrations of 0.09, 0.39, and 0.53 ,sM were obtained for carminomycin, Adriamycin, and carminomycin-i 1-methyl ether, respectively, using in vitro col ony survival studies against Novikoff hepatoma ascites cells. This ranking was not repeated for the other systems tested. The 50% inhibitory concentrations of Adriamycin for whole cellular nucleic acid syntheses were 2to 3-fold lower than those of carminomycin and over 10to 15-fold lower than those of carminomycin-i 1-methyl ether. The apparent binding con stants obtained for calf thymus DNA and salmon sperm DNA for Adriamycmnwere 3.67 x 106 and 11.68 x 106 M1, re spectively. Those obtained for carminomycin were 0.26 x 106 and 0.1 5 x 106 M― , respectively, and no detectable binding was observed for carminomycin-i 1-methyl ether. These find ings were confirmed by analysis of the effects of these anthra cyclines on superhelical PM-2 DNA by agarose gel electropho resis. Increasing concentrations of Adriamycin of up to 200 @LMprogressively decreased the superhelicity of PM-2 DNA in a manner typical of an intercalative binding agent, and concen trations 2to 5-fold and 20to 50-fold higher for carminomycin andits analog,respectively,wererequiredto obtainequivalent results. These results demonstrate that DNA-binding and nu cleic acid synthesis-inhibitory effects do not correlate with the antitumor action of carminomycin and its 11-methyl ether an alog. This suggests the importance of other subcellular targets, possibly distinct from those of Adriamycmn, which may be important in the cytotoxicity of carminomycin and its 11-methyl ether analog.