Circadian Timing in Cancer Treatments

Abstract

The circadian timing system is composed of molecular clocks, which drive 24-h changes in xenobiotic metabolism and detoxification, cell cycle events, DNA repair, apoptosis, and angiogenesis. The cellular circadian clocks are coordinated by endogenous physiological rhythms, so that they tick in synchrony in the host tissues that can be damaged by anticancer agents. As a result, circadian timing can modify 2- to 10-fold the tolerability of anticancer medications in experimental models and in cancer patients. Improved efficacy is also seen when drugs are given near their respective times of best tolerability, due to (a) inherently poor circadian entrainment of tumors and (b) persistent circadian entrainment of healthy tissues. Conversely, host clocks are disrupted whenever anticancer drugs are administered at their most toxic time. On the other hand, circadian disruption accelerates experimental and clinical cancer processes. Gender, circadian physiology, clock genes, and cell cycle critically affect outcome on cancer chronotherapeutics. Mathematical and systems biology approaches currently develop and integrate theoretical, experimental, and technological tools in order to further optimize and personalize the circadian administration of cancer treatments.

Los ritmos circadianos en cáncer y la cronoterapia

“…La quimioterapia es uno de los procedimientos más efectivos contra el cáncer (37). Los medicamentos antineoplásicos son diseñados para interrumpir la proliferación y supervivencia de las células tumorales, pero usualmente también afectan las células normales del paciente (38).…”

“…Los medicamentos antineoplásicos son diseñados para interrumpir la proliferación y supervivencia de las células tumorales, pero usualmente también afectan las células normales del paciente (38). Incluso las nuevas tecnologías que buscan tener blancos más específicos en las cé-lulas cancerosas, presentan efectos secundarios que interfieren en el tratamiento exitoso del cáncer o que, incluso, podrían ser fatales para los pacientes (37). Por esta razón ha sido necesaria la búsqueda de estrategias para contrarrestar los efectos adversos de estos medicamentos, por ejemplo, la cronofarmacología, o sea, la administración de tratamientos de acuerdo con los ritmos biológicos; su función consiste en aumentar la tolerancia y efectividad de los medicamentos mediante su administración a horas específicas del día (39).…”

Glucocorticoids and circadian clock control of cell proliferation: At the interface between three dynamic systems

“…So-called "chronotherapeutical" approaches increase the efficiency and reduce side effects of anti-cancer drugs. Cell proliferation rhythms are deregulated in many cancer types [70][71][72], and so delivering drugs that kill proliferating cells at a time when fewer normal cells divide will preferentially target the cancer cells that have escaped clock control. Another rationale for chronotherapy is linked to the metabolism of xenobiotics (such as cancer drugs): Degradation and modification of these substances is subject to circadian control.…”

“…Another rationale for chronotherapy is linked to the metabolism of xenobiotics (such as cancer drugs): Degradation and modification of these substances is subject to circadian control. Thus, giving a drug at the trough point of degradation activity will allow the A c c e p t e d M a n u s c r i p t use of overall lower doses, thereby reducing the potential side effects [72][73][74]. The beneficial effects of chronotherapeutics have now been demonstrated in various clinical trials (reviewed in [72]).…”

Statistical analysis of nonlinear dynamical systems using differential geometric sampling methods

“…Obtaining a detailed mechanistic understanding of such enzymatic control processes could have major implications in the study and potential treatment of disease at a molecular level. The circadian clock, for example, appears to play a central role in the physiology of plants and mammals, controlling many important cellular functions and influencing pathways implicated with a variety of diseases [15]; indeed the timing of drug administration relative to circadian rhythms appears to strongly affect the efficacy of certain anti-cancer agents [16]. Signalling pathways are also strongly implicated in the origin of many cancers [17] and understanding the intricate networks of nonlinear interactions is key to being able to predict the impact of biochemical changes within the system, whether natural or artificially induced with the use of drugs [18].…”