Tumor growth rate determines the timing of optimal chronomodulated treatment schedules.

Abstract

In host and cancer tissues, drug metabolism and susceptibility to drugs vary in a circadian (24 h) manner. In particular, the efficacy of a cell cycle specific (CCS) cytotoxic agent is affected by the daily modulation of cell cycle activity in the target tissues. Anti-cancer chronotherapy, in which treatments are administered at a particular time each day, aims at exploiting these biological rhythms to reduce toxicity and improve efficacy of the treatment. The circadian status, which is the timing of physiological and behavioral activity relative to daily environmental cues, largely determines the best timing of treatments. However, the influence of variations in tumor kinetics has not been considered in determining appropriate treatment schedules. We used a simple model for cell populations under chronomodulated treatment to identify which biological parameters are important for the successful design of a chronotherapy strategy. We show that the duration of the phase of the cell cycle targeted by the treatment and the cell proliferation rate are crucial in determining the best times to administer CCS drugs. Thus, optimal treatment times depend not only on the circadian status of the patient but also on the cell cycle kinetics of the tumor. Then, we developed a theoretical analysis of treatment outcome (TATO) to relate the circadian status and cell cycle kinetic parameters to the treatment outcomes. We show that the best and the worst CCS drug administration schedules are those with 24 h intervals, implying that 24 h chronomodulated treatments can be ineffective or even harmful if administered at wrong circadian times. We show that for certain tumors, administration times at intervals different from 24 h may reduce these risks without compromising overall efficacy.

• Authors: Samuel Bernard, Branka Cajavec Bernard, Francis Lévi, Hanspeter Herzel
• Journal: PLoS computational biology (PLoS Comput Biol) Vol. 6 Issue 3 Pg. e1000712 (Mar 19 2010) ISSN: 1553-7358 [Electronic] United States
• PMID: 20333244 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents

Topics

• Antineoplastic Agents (administration & dosage)
• Cell Cycle (drug effects)
• Circadian Rhythm (drug effects)
• Computer Simulation
• Drug Chronotherapy
• Humans
• Models, Biological
• Neoplasms (drug therapy, physiopathology)
• Outcome Assessment, Health Care (methods)
• Treatment Outcome