1. ¹INSERM E-0118 Chronothérapeutique des cancers and Université Paris XI, Institut du Cancer et d'Immunogénétique, Hôpital Paul Brousse, 14, av. Paul Vaillant Couturier, 94800 Villejuif, France
2. ²Aventis Pharma SA, Vitry Sur Seine, France
3. ³Oncologia Medica Complementare, Regina Elena Institute, Rome, Italy

Correspondence: Dr F Lévi, E-mail: chronbio@club-internet.fr

⁴TG Granda, R-M D'Attino and E Filipski contributed equally to this work.

Received 19 September 2001; Revised 17 December 2001; Accepted 7 January 2002.

Abstract

The relevance of circadian rhythms in irinotecan and oxaliplatin tolerability was investigated with regard to antitumour activity. Mice bearing Glasgow osteosarcoma (GOS) received single agent irinotecan (50 or 60 mg kg^-1 per day) or oxaliplatin (4 or 5.25 mg kg^-1 per day) at one of six dosing times expressed in hours after light onset (3, 7, 11, 15, 19 or 23 hours after light onset). Irinotecan (50 mg kg^-1 per day) and oxaliplatin (4 or 5.25 mg kg^-1 per day) were given 1 min apart at 7 or 15 hours after light onset, or at their respective times of best tolerability (7 hours after light onset for irinotecan and 15 hours after light onset for oxaliplatin) or worst tolerability (15 hours after light onset for irinotecan and 7 hours after light onset for oxaliplatin). Tumour growth rate was nearly halved and per cent increase in estimated life span (% ILS) was – doubled in the mice receiving irinotecan at 7 hours after light onset as compared to 15 hours after light onset (P<0.05). Results of similar magnitude were obtained with oxaliplatin for both endpoints, yet with 7 hours after light onset corresponding to least efficacy and 15 hours after light onset to best efficacy (P<0.05). Irinotecan addition to oxaliplatin proved therapeutic benefit only if the schedule consisted of irinotecan administration at 7 hours after light onset and oxaliplatin delivery at 15 hours after light onset, i.e. when both drugs were given near their respective 'best' circadian times. These would correspond to the middle of the night for irinotecan and the middle of the day for oxaliplatin in humans.