Relevance of circadian cell kinetics in the timing of chemotherapy in animal tumors.

Circadian rhythmicity in cell division has been proved in the actively proliferating healthy tissues of rodents (cornea, G.I.-tract, bone marrow, gonads, epidermis) as well as in most spontaneous or transplanted tumors growing in solid or ascites fluid phases. This circadian division accounts in part for the circadian varying sensitivity of healthy target tissues to oncolytic agents (chronotoxicity/chronotolerance). Similarly, antitumor activity as gauged from analysis of impact on cell kinetics and/or tumor shrinkage or cure was also shown to depend upon the dose and doing time of anticancer drug administration. Variations in the timing of internal cell kinetics after initial drug administration were also shown to depend on the type of drug (alkylating agent, antimitotic, or antimetabolite agent). Interestingly, internal desynchronization may occur in both healthy and tumor tissues, it may allow the selection of given circadian stages for the administration of a second drug at the point of highest tumor sensitivity and healthy tissue resistance (time of least sensitivity). These observations have been utilized to test strategies in sequential drug scheduling aimed at improving the overall therapeutic index. Observations indicate that in some instances these approaches could be translated to human beings.