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The cytostatic efficacy of the antibiotics adriamycin, daunomycin and actinomycin D and of DNA-complexes of these compounds was compared in an Ehrlich ascites tumor in vivo. Various doses of the individual drugs and their DNA-complexes were injected intraperitoneally into female NMRI mice following 8 days after inoculation of 10(6) Ehrlich ascites cells. Survival analyses of animals demonstrated that by addition of DNA therapeutic indices were improved for adriamycin, daunomycin and actinomycin D, DNA alone had no effect on this tumor. Since earlier biochemical data (Seeber et al., 1977) had shown decreased in vitro cytotoxicity of DNA-bound antibiotics, this increase in therapeutic efficacy is probably due to an altered pharmacological behaviour after complex formation with a prolongation of effective intraperitoneal drug levels and decreased systemic toxicity.

Inhibitory effects of adriamycin, daunomycin, actinomycin D and of the related DNA-complexes on DNA and RNA synthesis were compared by precursor uptake studies in Novikoff hepatoma cells, human mammary carcinoma cells and human leukemia cells. In addition, nuclear RNA labelling profiles were analyzed in human acute leukemia blast cells and nucleolar RNA synthesis was studied in Novikoff hepatoma cells in vitro after incubations of the tumor cells with adriamycin and DNA-adriamycin. The studies revealed that compared to the free drugs a) the DNA complexes were generally less active with respect to inhibition of overall DNA and RNA synthesis in these divergent tumor cell types, b) characteristic differences between adriamycin and daunomycin which are related to a more rapid cellular uptake of daunomycin were still present after complexing of both drugs to calf thymus DNA, and c) the intracellular mode of action of the free antibiotics was not changed by complex formation with DNA. These results indicate that a preferential incorporation of the macromolecular complexes into the tumor cells by pinocytosis--as originally postulated by Trouet et al. (1972)--is not likely for Novikoff hepatoma cells, human mammary carcinoma cells and human acute leukemia blast cells. In contrast, it may be concluded from this study that the DNA complexes dissociate already at the outer cell membrane resulting in a generally decreased but kinetically drug-specific cellular uptake. In a second communication it will be demonstrated that these in-vitro effects do not correlate with the therapeutic efficacy efficacy of the complexed drugs in vivo.