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Synergistic Effect of Ricin in Combination with Daunorubicin, cis-Dichlorodiammineplatinum(II) and Vincristine in Systemic L1210 Leukemia

Norsk Hydro's Institute for Cancer Research and The Norwegian Cancer Society, Montebello, Oslo 3, Norway

The antitumor effect of combinations of the toxic proteins ricin and abrin with other drugs was studied in mice with systemic L1210 leukemia. Ricin was tested in combination with daunorubicin, cis-dichlorodiammineplatinum(II), or vincristine, and abrin was tested in combination with Adriamycin. The antileukemic effect of the regimens was gauged by assaying the life span of tumor-bearing animals and by measuring the survival of leukemic cells in bone marrow, spleen, and brain by end point dilution assay. The effect of the drugs on leukemic cells was compared with that on resting and proliferating normal bone marrow cells in spleen colony assays.

Administration of a fixed dose of ricin (1 µg/kg) enhanced considerably the antileukemic effects of the conventional drugs given concurrently without increasing their toxicity. With daunorubicin and cis-dichlorodiammineplatinum(II), ricin increased the leukemic cell kill in the bone marrow by factors of about 10 and 5, respectively. With vincristine, ricin increased the cell kill in bone marrow and spleen up to several hundred-fold, as measured by end point dilution. Also the life span of the animals was increased by ricin, but not corresponding to the increased cell kill in the bone marrow and spleen, probably due to inability of the drugs to pass the blood-brain barrier. Abrin-Adriamycin combinations were approximately as effective against leukemic cells in the bone marrow as has been observed previously for ricin-Adriamycin combinations.

End point dilution and spleen colony assays gave concordant results with respect to survival of leukemic bone marrow cells, except when vincristine was given alone. In this case, the apparent cell kill, as measured by spleen colony assay, was greater than that measured by end point dilution assay. The results suggest that vincristine may partially damage the leukemic cells, rendering them unable to colonize spleens, while they still retain the ability to multiply in the peritoneal cavity of recipient animals. When ricin was administered concurrently with vincristine, no discrepancy between the 2 assays was found.

The results demonstrate a true potentiation of combinations of ricin with cancerostatic drugs belonging to several different classes, and they suggest that the same may be the case with abrin combinations.

¹ Present address: Laboratory of Experimental Therapeutics and Metabolism, National Cancer Institute, NIH, Bethesda, Md. 20205.

Received 9/ 1/81. Accepted 2/25/82.