Synergistic effect of adriamycin and ricin on L1210 leukemic cells in mice.

The effect of Adriamycin and ricin, singly and together, on the survival of L1210 leukemic cells in mice has been assessed by spleen colony and end-point dilution assays. Adriamycin, as well as ricin, had a stronger effect on leukemic than on normal bone marrow cells. Rapidly proliferating normal cells were as sensitive to Adriamycin as were the leukemic bone marrow cells. In contrast, the preferential effect of ricin was not proliferation dependent. Combinations of Adriamycin and ricin gave a less than ad ditive toxicity, as measured by the survival of nonleukemic mice. In mice with systemic leukemia, combinations of Adria mycin and ricin exhibited a synergistic effect on the life span of the animals, corresponding to a reduction in the leukemic cell burden by 1 to 2 logs. In the bone marrow, the synergism amounted to a reduction in the fraction of surviving leukemic cells by up to 5 logs, whereas in liver, spleen, and brain the synergism was several orders of magnitude lower. The combi nations showed no increased effect on resting normal bone marrow cells, and only an additive effect on rapidly proliferating normal cells. In mice inoculated with leukemic cells intracerebrally, i.v. administration of either Adriamycin or ricin did not affect the survival, whereas the combination definitely increased the life span of the animals. In experiments on L1210 cells in culture, only a moderate synergistic effect was found, of a magnitude similar to that found for the liver and spleen of leukemic animals treated in vivo. Similar results were obtained when leukemic bone marrow was exposed in vitro and the effect on the leukemic cells was assayed in vivo. The results indicate that the observed synergistic effect of Adriamycin and ricin is due to some special property of the leukemic cells and cannot be accounted for by their rapid rate of proliferation. Conceivably, the presence of one agent facili tates the entry of the other one into the cells. The activity of the combination in intracerebral leukemia may involve an effect on the blood-brain barrier. The particular high potentiation ob served in the bone marrow remains unexplained.