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Effect of Combination Treatment with 5-Azacytidine and Cytidine on the Life-Span and Spleen and Bone Marrow Cells of Leukemic (L1210) and Nonleukemic Mice¹

Microbiological Associates, Inc. [S. V., J. N. C., V. S. W., and I. K.]; and Chemotherapy, National Cancer Institute [A. G.], Bethesda, Maryland 20014

Investigations were carried out to examine the antileukemic effect of 5-azacytidine, a synthetic analog of cytidine. The effect of cytidine and deoxycytidine upon the antileukemic activity and toxicity of 5-azacytidine was also investigated. Treatment from Days 3 to 7 and 3 to 11 with optimal doses of 5-azacytidine increased the life-span of the leukemic mice by 85 to 100% over that of the untreated leukemic controls. Mice treated with doses above the optimum succumbed from the toxic effects of the drug.

Simultaneous treatment with cytidine (600 or 360 mg/kg) reversed the antileukemic activity of optimal doses of 5-azacytidine. This treatment also reduced the toxicity of higher doses of 5-azacytidine (12 to 33 mg/kg) to leukemic mice, permitting the observations of increased survival time of these mice, and completely reversed the toxicity of the drug to nonleukemic mice.

Spleen and bone marrow cells of leukemic and non-leukemic mice treated with 5-azacytidine were significantly reduced below the levels of untreated controls. However, the results indicate that the optimal doses of 5-azacytidine (2.6 and 4.3 mg/kg) were more active against rapidly proliferating leukemic cells than nonleukemic cells. Concurrent treatment with cytidine restored the spleen and bone marrow cells of leukemic and nonleukemic mice and also the colony-forming capability of nonleukemic cells.

With deoxycytidine instead of cytidine in combination treatment with 5-azacytidine, only minor effects were observed in lowering antileukemic activity and host toxicity of the drug.

¹ This study was supported in part by Contract PH-43-68-1283 with Chemotherapy, National Cancer Institute, USPHS.

Received 5/19/69. Accepted 6/20/69.