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Schedule-dependent Synergism for the Combination of 1-ß-D-Arabinofuranosylcytosine and Daunorubicin¹

Section of Cancer Biology, Mallinckrodt Institute of Radiology [M. E., F. V.], and Division of Hematology and Oncology, Mallinckrodt Department of Pediatrics [T. V.], Washington University School of Medicine, St. Louis, Missouri 63110.

Studies utilizing the spleen colony assay for both leukemic and normal hematopoietic colony-forming units indicate that the effectiveness of the combination of 1-ß-D-arabinofuranosylcytosine (ara-C) and daunorubicin (Daun) in killing leukemic cells is highly schedule dependent. When the two agents are given simultaneously, the degree of cell kill is less than additive; that is, the level of survival is greater than that given by the product of the leukemic colony-forming unit survival for the two agents used separately. When Daun is given before ara-C, the resulting cell kill is additive. However, if, Daun is given from 2 to 40 hr after ara-C, a marked increase in cell kill occurs reaching a maximum when the two agents are given 15 hr apart. The survival of normal colony-forming units utilizing the same doses in combination is never less than that defined as additive. Studies using different doses of ara-C and Daun with an optimum time interval between drug administration indicate that the synergism observed for the leukemic colony forming units is dependent upon the doses of both agents.

¹ This work was supported by USPHS Grant 1P02CA13053 from the National Cancer Institute and Grant GM02016 from the NIH and by the Fern Waldman Memorial Fund.

Received 7/11/73. Accepted 10/25/73.