Preclinical relevance of dosing time for the therapeutic index of gemcitabine–cisplatin

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 HALO±cisplatin (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 HALO±cisplatin (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.