1. ¹INSERM E 354 'Chronothérapeutique des Cancers' and Université Paris XI, Hôpital Paul Brousse, 14-16 Avenue Paul Vaillant Couturier, Villejuif 94800, France
2. ²Department of Surgery, Yokohama City University Hospital, Yokohama 236-0004, Japan
3. ³Department of Applied Technology, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China
4. ⁴Eli Lilly and Co., Indianapolis, Indiana 46225, USA
5. ⁵Chronotherapy Group of European Organization for Research and Treatment of Cancer, Les Cliniques Saint Joseph, 4000 Liège, Belgium

Correspondence: Dr XM Li, E-mail: li@vjf.inserm.fr

Revised 23 February 2005; Accepted 14 March 2005; Published online 19 April 2005.

Abstract

The relevance of gemcitabine timing for chronotherapeutic optimisation was investigated. Healthy mice received multiple doses of gemcitabine (120, 160 or 200 mg kg^-1 injection (inj)^-1) at one of six circadian times (3, 7, 11, 15, 19 or 23 h after light onset – HALO) on days 1, 4, 7 and 10 or a single dose of gemcitabine (400 mg kg^-1) at 11 or 23 HALOcisplatin (5 mg kg^-1 at 1 min, 4 or 8 h later). Mice bearing Glasgow osteosarcoma received multiple doses of gemcitabine (200 mg kg^-1 inj^-1) at 11 or 23 HALOcisplatin (5 mg kg^-1 inj^-1 at 1 min or 4 h later) on days of 10, 13, 16 and 19 following tumour inoculation. A circadian rhythm in body weight loss was statistically validated, with 1030 HALO corresponding to the least toxic time (95% CL, 0800 to 1300). Gemcitabine dosing produced least body weight loss and least neutropenia after injection at 11 vs 23 HALO, whether the drug was given alone or with cisplatin (P=0.001). Gemcitabine–cisplatin tolerability was improved by dosing gemcitabine at 11 HALO and CDDP at 15 HALO (P<0.001). The administration of this schedule to tumour-bearing mice increased median survival three-fold as compared to treatments where both drugs were given simultaneously at 11 or 23 HALO (P=0.02). The optimal schedule would correspond to the delivery of gemcitabine upon awakening and cisplatin near mid-activity in cancer patients.