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Circadian Stage Dependence of cis-Diamminedichloroplatinum Lethal Toxicity in Rats¹

Departments of Medicine [W. J. M. H., F. A. L., B. J. K.] and Laboratory Medicine and Pathology [F. H.], Section of Medical Oncology and Chronobiology Laboratories, University of Minnesota, Minneapolis, Minnesota 55455

Renal physiology is circadian rhythmic. The major toxicity of cis-diamminedichloroplatinum (cisplatin) is irreversible renal damage. A single dose of cisplatin (11 mg/kg) was given to groups of standardized female Fischer 344 rats at one of six equispaced circadian stages. A statistically significant effect of time of injection upon tolerance was found by X² analysis. Differences of 3- to 8-fold in survival rate at 50% mortality and a nearly 3-fold difference in long-term survival depended on circadian timing of cisplatin administration. Cisplatin timing resulting in optimal tolerance was similar from study to study.

Additional 0.9% NaCl solution was administered with cisplatin in three experiments and resulted in an increase in overall mean survival time. It also resulted in an amplification of the survival rhythm without changing its timing. The increase in survival resulting from 0.9% NaCl solution loading, when compared to controls receiving cisplatin alone, was also highly time dependent. A 52% improvement in mean survival time was achieved in those animals receiving cisplatin and 0.9% NaCl solution at the most favorable circadian stage, as compared to a 20% improvement when this regimen was administered at an inopportune circadian stage. The safest time for cisplatin administration is near the midactivity span, shortly after the maximum of the circadian rhythm in rectal temperature.

¹ This work was supported by National Cancer Institute Grant CA-14445; the Masonic Memorial Hospital Fund, Inc.; the Minnesota Medical Foundation; and the American Cancer Society.

² American Cancer Society Junior Faculty Fellow, Grant 509A. To whom requests for reprints should be addressed.

³ Recipient of a fellowship grant from the Daughters of Job of the Minnesota Masons.

Received 2/ 5/81. Accepted 12/19/81.

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