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

Abstract

The relevance of gemcitabine timing for chronotherapeutic optimisation was investigated. Healthy mice received multiple doses of gemcitabine (120, 160 or 200 mg kg À1 injection (inj) À1 ) 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 À1 ) at 11 or 23 HALO7cisplatin (5 mg kg À1 at 1 min, 4 or 8 h later). Mice bearing Glasgow osteosarcoma received multiple doses of gemcitabine (200 mg kg À1 inj À1 ) at 11 or 23 HALO7cisplatin (5 mg kg À1 inj À1 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 ¼ 0.001). Gemcitabine -cisplatin tolerability was improved by dosing gemcitabine at 11 HALO and CDDP at 15 HALO (Po0.001). 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 ¼ 0.02). The optimal schedule would correspond to the delivery of gemcitabine upon awakening and cisplatin near mid-activity in cancer patients.

Chronopharmacologic Cancer Treatment with an Angiogenic Vessel-Targeted Liposomal Drug

“…[20][21][22][23] Anticancer drugs are also chronologically considered for scheduling to reduce side effects and enhance antitumor activity. [24][25][26][27][28] These results indicate that the susceptibility of tumor cells to anticancer agents oscillates. Moreover, the efficacy of antiangiogenic therapy depends on dosing time, 14,29) since the previous report suggested that VEGF production also fluctuates in a circadian fashion.…”

Circadian Timing in Cancer Treatments

“…Dedicated chronobiologic animal facilities allow setup light onset at the desired time for different groups of animals located on different isolated shelves, so that different circadian stages are tested at the most convenient times (46). Figure 3 depicts the times of least toxicity and benefit from optimal circadian timing, referring to external LD synchronizer and internal average body temperature rhythm for 16 anticancer drugs in male B6D2F1 mice (female C57BL/6 × male DBA2) in studies performed at our laboratory (47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63). The optimal circadian timings are staggered along the 24-h period and cannot be predicted thus far by the knowledge of pharmacologic class or that of main target organs for toxicity.…”

“…Circadian rhythms in the tolerability of anticancer drugs persist in rodents kept in constant darkness or in constant light, which demonstrates their endogenicity (64). Even when combined, chemotherapeutic agents display the least toxicity near their respective times of best tolerability as single agents, as shown for doxorubicin-cisplatin in Lou rats, irinotecanoxaliplatin or gemcitabine-cisplatin in B6D2F1 mice, and docetaxel-doxorubicin in C3H/He mice (56,(65)(66)(67). These findings support the persistence of the circadian control of anticancer drug determinants after exposure to the first anticancer agent, at least when the latter is given near the time of best tolerability.…”

“…An opposite pattern characterizes proapoptotic BAX, with a fivefold 24-h change and a peak at ZT15 (33). The temporary arrest of cycling cells in G0-G1, the high BCL2, and low BAX expressions during the light span when mice rest help explain the best circadian timing for the tolerability of 5-FU, gemcitabine, irinotecan, and docetaxel in male B6D2F1 mice (48,56,58,67,73). However, the circadian control of drug metabolism and detoxification also profoundly modifies the cellular exposure to these medications, whose molecular targets are usually clock regulated (77,88).…”

The antitumor activity of an anti‐CD54 antibody in SCID mice xenografted with human breast, prostate, non‐small cell lung, and pancreatic tumor cell lines

“…Therapy was repeated once every 7 days for a total of 4 injections. The dose of gemcitabine used was based on the reported [43][44][45] and confirmed LD 50 of 500 mg/kg mouse (data not shown). UV3, gemcitabine, and the combination were all more effective than the control (p < 0.05).…”