Research on cancer chronotherapy started in France in 1982 at Hôpital Paul Brousse (Villejuif). Dr Francis Lévi had just returned from a 3-year position in the Chronobiology Laboratory of Pr Franz Halberg (Minneapolis, USA), a pioneer of this field. Pr Georges Mathé, founder of cancerology in Europe and Head of the "Institut du Cancer et d’Immunogénétique (ICIG)",  and Pr Alain Reinberg (CNRS), offered him to start his own laboratory at hôpital Paul Brousse, to develop both fundamental and clinical research on the role of circadian rhythms in the activity of antitumor treatments. Hired in 1982 by the CNRS, Dr Lévi perform mouse experiments to test the chronopharamcology of new anticancer drugs which are further validated in cancer patients by Pr Mathé's unit.

The laboratory of "Chronothérapeutique des Cancers" then became the INSERM unit 776 « Rythmes Biologiques et Cancers »  (RBC) and is now the Team 3 in the INSERM unit 935. Our Laboratory demonstrated in collaboration with several pharamcological industrial partners that the tolerability of 19 anticancer agent varied by 50 to 500% according to the circadian time of administration in mice (Figure 1).


Figure 1 : Circadian Administration Timing corresponding to the best tolerance of anticacenr chemotherapies in mice subjected to 12h:12h light-dark cycles.

Several molecular mechanisms are discovered which drive drug chronopharmacology- that is the circadian rhythms of the drug fate in the body (or chronopharmacokinetics) and of the drug efficacy on healthy or tumor tissues (or chonopharmacodynamics). From 1984, our laboratory conducted experimental and clinical studies aiming to improve anticancer treatments by accounting for biological rhythms. The first clinical trials demonstrated that the association of two drugs, theprubicin and cisplatin, was less toxic when administered at 6am and between 2pm and 6pm respectively compared to administration times shifted by 12h.

Next, the investigation of circadian rhythms of individual patients revealed an important alteration of rhythms of plasma cortisol levels and circulating white blood cells in 1/3 of patients with advanced or metastatic breast or ovarian cancers. This finding may explain why certain patients may benefit from chronomodulated infusion whereas other patients with disrupted rhyhtms may not


The concomittent developement of the drug oxaliplatin and of programmable pumps for drug infusion played a critical role in the international recognition of our laboratory and of its Research fields (Figure 2). Our laboratory studied the chronopharmacology of oxaliplatin which was originaly thought too toxic to be developed for the clinics. In 1990, our team showed an improved drug tolerability thanks to a chronomodulated sinusoidal drug infusion scheme between 2pm and 6pm, compared to constant administration. In the following years, clinical trials conducted by our laboratory demonstrated an improved antitumor efficacy of oxaliplatin thanks to chronomodulated adminsitration, in association with 5-fluorouracil and folinic acid (Lévi et al. 1992Lévi et al. 1994 ; Lévi et al. 1997 ). The "Groupe de Chronothérapie"  was then created and gathered approximately 40 European cancer centres. They performed more than 25 clinical trials to test the relevance of cancer chronotherapy compared to non-circadian based protocols.


Figure 2 :  5-fluorouracil/Oxaliplatin Chronotherapy. Increased tolerability and antitumor efficacy of the association of oxaliplatin and 5-Fluorouracil- folinic acid compared to constant perfusion in metastatic colorectal cancer patients.




Unité INSERM U935

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