DOCETAXEL CHRONOPHARMACOLOGY IN MICE

Docetaxel tolerance and antitumor efficacy could be enhanced if drug a dministration was adapted to circadian rhythms. This hypothesis was in vestigated in seven experiments involving a total of 626 male B6D2F(1) mice, synchronized with an alternation of 12 h of light and 12 h of d arkness (12:12), after i.v. administration of docetaxel. In experiment (Exp) I, the drug was given once a week (wk) for 6 wks (20 mg/kg/wk) or for 5 wks (30 mg/kg/wk) at one of six circadian times, during light when mice were resting [3, 7, or 11 hours after light onset (HALO)], or during darkness, when mice were active (15, 19, or 23 HALO). Endpoi nts were survival and body weight change. In Exp 2 and 3, docetaxel (3 0 mg/kg/wk) was administered twice, 1 wk apart, at one of four circadi an stages (7, 11, 19, or 23 HALO). Endpoints were hematological and in testinal toxicities. In Exp 4, circadian changes in cell cycle phase d istribution and BCL-2 immunofluorescence were investigated in bone mar row as possible mechanisms of docetaxel tolerability rhythm. In Exp 5 to 7, docetaxel was administered to mice bearing measurable P03 pancre atic adenocarcinoma (270-370 mg), with tumor weight and survival as en dpoints. Mice from Exp 5 and 6 received a weekly schedule of docetaxel at one of six circadian stages (20 or 30 mg/kg/wk at 3, 7, 11, 15, 19 , or 23 HALO). In Exp 7, docetaxel (30 mg/kg) was given every 2 days ( day 1, 3, 5 schedule) at 7, 11, 19, or 23 HALO. Docetaxel dosing in th e second half of darkness (19 or 23 HALO) resulted in significantly wo rse toxicity than its administration during the light span (3, 7, or 1 1 HALO). The survival rate ranged from 56.3% in the mice treated at 23 HALO to 93.8 or 87.5% in those injected at 3 or 11 HALO, respectively (Exp 1, P < 0.01). Granulocytopenia at nadir was -49 +/- 14% at 7 HAL O compared with -84 +/- 3% at 19 HALO (Exp 2 and 3, P < 0.029), and se vere jejunal mucosa necrosis occurred in 5 of 8 mice treated at 23 HAL O as opposed to 2 of 18 receiving docetaxel at 7, 1!, or 19 HALO (Exp 2 and 3, P < 0.02). The time of least docetaxel toxicity corresponded to the circadian nadir in S or G(2)-M phase and to the circadian maxim um in BCL-2 immunofluorescence in bone marrow. Docetaxel increased the median survival of tumor-bearing mice in a dose-dependent manner (con trols: 24 days; 20 mg/kg weekly, 33 days; 30 mg/kg weekly or day 1, 3, 5 schedule, 44 or 46 days, respectively; Exp 5-7). Survival curves of treated mice differed significantly according to dosing time fur each dose and schedule (P from log rank < 0.003 to P < 0.03). In Esp 5 and 6, the percentage of increase in life span was largest if docetaxel w as administered weekly at 7 HALO (20 mg/kg, 220%; 30 mg/kg, 372%) and lowest after docetaxel dosing at 19 HALO (80% with 20 mg/kg) or at 15 HALO (78% with 30 mg/kg). In Exp 7, (day 1, 3, 5 schedule), docetaxel was most active at 11 HALO (percentage increase in life span, 390%) an d least active at 23 HALO (210%). Docetaxel tolerability and antitumor efficacy were simultaneously enhanced by drug dosing in the light spa n, when mice were resting. Mechanisms underlying the tolerability rhyt hm likely involved the circadian organization of cell cycle regulation . Docetaxel therapeutic index may be improved with an administration a t night in cancer patients, when fewest bone marrow cells are in S or G(2)-M phase.