Chronotherapy for Cancer Treatment


Cancer is a generic term for a large group of diseases that can affect any part of the body. Other terms used are malignant tumours and neoplasms. Chronotherapeutics or chronotherapy, is the synchronization of medication with the biological rhythms of disease activity and symptom intensity. In general, chronotherapeutics refers to treating a patient according to a person's daily, monthly, seasonal, or yearly biological clock, in order to maximize the health benefits and minimize adverse effects. Chronopharmacology is the investigative science concerned with the effects of drugs upon the timing of biological events and rhythms. It also links effects of drugs on biological timing to get the dynamic activity. Chronopharmacokinetics is subdivision of chronopharmacology which deals with the study of the temporal changes in the pharmacokinetics of the drugs with respective time. It is clear that daily synchrony between day and night cycles and circadian rhythms is essential for the optimization of metabolism and energy utilization for sustaining of life processes. Biological processes including the sleep-wake cycle, controlled by pacemaker which is present in the suprachiasmatic nuclei(SCN) in mammals. Due to alterations in biological activities With respect to time, the pathophysiology of many diseases like allergic rhinitis, arthritis, asthma, cardiovascular diseases, peptic ulcer disease, etc., results in exacerbation of symptoms. Circadian rhythms, physiology, and behavior of mammalian bodies are controlled by clock genes namely Per1, Per2 and Per3, which are rhythmically expressed in the SCN. The clock genes are present in peripheral tissue also. Recent experiment has revealed that there are many genes expressing a circadian rhythm in the liver. The liver is a biological clock capable of creating its own circadian rhythms and governs daily biochemical and physiological processes.

Many drugs are still given without regard to the time of day. To increase the therapeutic benefit and reduce the side effects of pharmaceuticals, monitoring of markers such as clock genes may be useful to choose the most appropriate time of day for administration of drugs. Food and Drug Administration (FDA) has suggested additional parameters for chronotherapeutics clinical studies such as:

  1. Drug administration time of the day.
  2. Patient's normal habits and sleep patterns.
  3. Biological factors which are time-related, like seasonal disorders.

The delivery of medications according to circadian rhythms has shown clinical benefits in randomized trials involving large number of patients with cancer, rheumatologic, cardiovascular, or allergic diseases. However, inter- and intrapatient variabilities have been demonstrated regarding the circadian timing system that governs chronotherapeutics mechanisms. Dedicated systems biology/medicine methodologies enable such challenges to be handled through the integration of patient-specific key parameters within a unique mathematical framework for the design of personalized pharmacotherapies. Systems chronotherapeutics thus represent a conceptual and methodological advance for making chronotherapeutics fit for each individual patient. As such, it will expectedly greatly impact on patients’ health due to the joint improvement in tolerability and efficacy, resulting from the moderation of treatment dynamics by patient- and disease-specific parameters, as well as by therapeutic strategy. This is in sharp contrast with current treatment paradigms, which remain mostly based on empiricism, standardization, snapshot assessments, and reactive decisions. Additionally, systems chronotherapeutics will allow for the reduction of medical complications due to the delivery of even complex treatments on a full outpatient basis. The continuous monitoring of patient well-being and disease in real time. Indeed, the combination of complex chronotherapeutic administration at home, with multidimensional telemonitoring, and timely behavioral tutoring would support chronic disease patients and their families to enjoy improved daily life, through reduced adverse events, and better efficacy.

Pharmaceutical and biomedical industries also have great interest in endorsing multidisciplinary systems chronotherapeutic as a cost-effective mean to improve drug development, which currently has a high failure rate. Indeed physiologically-based mathematical models can be developed to assess patient-specific drug chrono-efficacy and chrono-tolerability from multi-type datasets measured through dedicated biomedical devices. Thus, this type of modeling allows for a priori in silico test of therapeutic response of individual patients to a specific drug combination and/or timing, thus providing a critical tool to assist the clinician’s decision to include a particular patient in a clinical trial. Ultimately, physiologically-based models can be used in optimization procedures to design personalization frameworks taking as inputs multitype datasets in the individual subject and outputting patient-tailored chronomodulated treatments. After its design though preclinical and clinical steps, the personalization algorithm needs to be validated through several clinical stages. As a result, systems chronotherapeutics represent a new methodology for the design of clinical trials, in which each individual patient would receive individualized chronomodulated therapies computed by data-driven mathematical models, a novel approach in need of clinical validation.