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Survival and Cure of Leukemic Mice after Circadian Optimization of Treatment with Cyclophosphamide and 1-ß-D-Arabinofuranosylcytosine¹

Department of Anatomy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72201 [L. E. S., E. R. B., J. E. P.]; Chronobiology Laboratories, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota 55455 [F. H.]; and Department of Anatomic and Clinical Pathology, St. Paul-Ramsey Hospital, St. Paul, Minnesota 55101 [E. H.]

When cyclophosphamide and 1-ß-D-arabinofuranosylcytosine were administered to mice previously given injections of L1210 leukemia cells, the combination was more effective than either drug given alone. The effectiveness of the 2 drugs in combination was strongly influenced by the stage of the circadian system at which the drugs were administered. With the use of a chronobiological (sinusoidal) approach, in comparison with one or two conventional treatment schedules, it was possible to demonstrate an overall lower toxicity as monitored by death or weight loss. In general, mean survival times and cures (when obtained) were circadian stage dependent; for example, in 1 study the cure rate was 94% in mice treated at 1 circadian stage, but only 44% in those treated at another stage. It cannot be overemphasized, however, that just as the "right" timing can enhance (with statistical significance) both the tolerance to chemotherapeutic agents and the rate of cure in leukemic mice, so can the "wrongly" timed (wrongly placed) ara-C sinusoid or "wrongly" timed cyclophosphamide enhance toxicity and host death rate.

¹ Supported in part by Grants CA-14388 and CA-14445 from the National Cancer Institute.

² Recipient of Research Career Development Award CA 70594 from the National Cancer Institute.

Received 9/27/76. Accepted 7/ 6/77.