Experimental chronotherapy of mouse mammary adenocarcinoma MA13/C with docetaxel and doxorubicin as single agents and in combination

The therapeutic index of docetaxel, doxorubicin and their combination may b e improved by an adequate selection of the circadian time of administration . The present study constitutes a prerequisite to testing the clinical rele vance of chronotherapy in human breast ranter. Three experiments were perfo rmed in C3H/HeN mice. Each treatment modality was administered i.v, once a week for 3 weeks at one of six circadian stages, during the light span, whe n the mice were resting: 3, 7, and 11 h after light onset (HALO), or during darkness, when the mice were active: 15, 19, and 23 HALO, The circadian ti me dependency of single agent tolerability was investigated in healthy mice using four dose levels for docetaxel (38.8, 23.3, 14, and 8.4 mg/kg/inject ion) and for doxorubicin (13.8, 8.3, 5 and 3 mg/kg/injection; experiment 1) . The circadian time dependency of each single agent efficacy was studied i n MA13/C-bearing mice, using two dose levels of docetaxel (38.8 or 23.3 mg/ kg/injection) or doxorubicin (8.3 or 5 mg/kg/injection; experiment 2), The toxicity and the efficacy of the simultaneous docetaxel-doxorubicin combina tion were assessed as a function of dosing time in experiment 3. Two combin ations were tested (A, 16.3 mg/kg/injection of docetaxel and 2.5 mg/kg/inje ction of doxorubicin; and B. 11.6 and 3.5 mg/kg/injection, respectively) at each of the above six circadian times. Mortality, body weight change, and tumor size were recorded for 60-70 days in each experiment. Single agent do cetaxel or doxorubicin was significantly best tolerated near the middle of the rest span (7 HALO) and most toxic in the middle of the activity phase ( 19 HALO). Docetaxel or doxorubicin as a single drug were also most effectiv e at 7 HALO, irrespective of dose. Treatment at 7 HALO produced highest rat es of complete tumor inhibition (81% versus 11% at 3 HALO for docetaxel, p from chi (2) <0.001, and 69% versus 44% at 11 HALO for doxorubicin. not sig nificant) and highest day 60 survival rate (100% versus 28% at 3 HALO for d ocetaxel, p from <chi>(2) <0.001 and 89% versus 69% at 15 HALO for doxorubi cin, not significant). Docetaxel-doxorubicin combinations were most effecti ve following dosing in the beginning of the rest span or short after the on set of the activity span, with regard to the rates of both complete tumor i nhibitions (45% at 3 HALO versus 15% at 19 HALO) and day 70 survival rates (85% and 80% at 3 and 7 HALO respectively, versus 20% at 19 HALO). The effi cacy of single agent docetaxel or doxorubicin and that of their combination varied largely as a function of circadian dosing time. Single agent doceta xel at 7 HALO was the best treatment option in this model with regard to bo th tolerability and efficacy. This timing may correspond to the middle of t he night in cancer patients.