Close reproduction by different laboratories of characteristics of circadian rhythm in 1-beta-D-arabinofuranosylcytosine tolerance by mice

Abstract

The tolerance of BALB/c X DBA/2 F1 mice to the popular cytostatic drug 1-beta-D-arabinofuranosylcytosine (ara-C) was tested in two laboratories about 1000 km apart. According to the same plan and on the same days in Little Rock, Ark., and Minneapolis, Minn., nine groups of 20 mice each received four courses of ara-C treatment, with 4-day intervals between them beginning February 7, 1973. In each course, a total dose of 240 mg/kg was divided among eight separate injections administered at 3-hr intervals. One group of mice received equal doses of ara-C every 3 hr (the homeostatic schedule). The eight other groups in each location received the same total dose per course but in gradually increasing and decreasing doses (the sinusoidal schedule). The timing of the highest doses on the latter schedule differed among the eight groups (by integer multiples of 3 hr). As predicted from earlier work, survival times after treatment with ara-C on different sinusoidal schedules differed drastically. However, the timing of the sinusoidal schedules yielding the longest survival was similar in the two locations. The survival times from all sinusoidal treatments from a given location were fitted by a 24-hr cosine curve. The timing of the rhythm in tolerance as a whole as thereby computed as the lag from local midnight of the peak in the cosine curve best fitting all data. The timing of this tolerance rhythm (briefly, circadian chronotolerance), computed separately for data from Arkansas and Minnesota, agreed within 1 hr. There also was close agreement in the results obtained by the 2 laboratories in mean survival time; the percentage of survivors when mice were treated according to certain of the selected sinusoidal schedules was much greater than for mice treated on the homeostatic schedule. This large and reproducible difference in tolerance and the similar timing of the overall fitted function describing chronotolerance in the hands of different investigators underlines the urgency of testing potential benefits from timed clinical treatment.