Circadian optimisation of irinotecan and oxaliplatin efficacy in mice with Glasgow osteosarcoma

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 71 per day) or oxaliplatin (4 or 5.25 mg kg 71 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 71 per day) and oxaliplatin (4 or 5.25 mg kg 71 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 (P50.05). 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 (P50.05). 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.

A phase II study of irinotecan plus chronomodulated oxaliplatin, 5-fluorouracil and folinic acid in advanced colorectal cancer patients

“…In this context, our group previously demonstrated in an experimental mouse model that the synergy between CPT-11 and L-OHP is obtained only when the two drugs are given at their optimal timing, which is during the second half of activity span for L-OHP and during the second half of rest span for CPT-11, coming to a peak time of 1600 for L-OHP and of 0500 for CPT-11 in human beings (Granda et al, 2002). At this time, there is no clear evidence that CPT-11 chronomodulation can help to significantly increase effectiveness or tolerability of this drug, when it is used alone or in combination with 5-FU and it is compared to the standard 1-h infusion regardless of peak timing Giachetti et al, 2001).…”

Chronomodulated Irinotecan, Oxaliplatin, and Leucovorin-Modulated 5-Fluorouracil as Ambulatory Salvage Therapy in Patients with Irinotecan- and Oxaliplatin-Resistant Metastatic Colorectal Cancer

“…However, the severe toxicities encountered with these regimens limit their use. In tumor-bearing mice, though, the combination of irinotecan and oxaliplatin was both synergistic and nontoxic when irinotecan and oxaliplatin were administered at their respective least toxic circadian times, that is, near the end of the rest span for irinotecan and near the middle of the activity span for oxaliplatin [20]. Based on the circadian time structure of mouse and human species, these times, respectively, correspond to 5 a.m., that is, in the second half of sleep, and 4 p.m., that is, near the middle of wakefulness in humans.…”

“…Chronotherapy of human CRC is based on the demonstration of circadian time dependencies in the pharmacology, toxicology, and therapeutic efficacy of 5-fluorouracil/leucovorin (5-FU/LV), oxaliplatin, and irinotecan in experimental models and/or in cancer patients [1,2,[15][16][17][18][19][20][21][22]. The control of cell proliferation by the circadian timing system represents an essential mechanism that determines optimal drug delivery timing.…”

Optimisation of time-scheduled regimen for anti-cancer drug infusion

“…Oxaliplatin, one of the few drugs active on metastatic colorectal cancer, is also known to be active on Glasgow osteosarcoma in mice. This murine tumour, transplanted under the skin of the animal, is easily measurable at the laboratory with a caliper, which allows obtaining tumour growth curves, with or without treatment, in whole living animals [18] (animals in which tumours had reached 10% of their total body weight were sacrificed for ethical reasons).…”

“…The efficacy or toxicity function describing the cell kill effect was chosen of the Hill type, taking into account pharmacological uses and recent published studies [13,30], its maximum being modulated by a 24 h-periodic cosine representing circadian pharmacosensitivity. Tissue pharmacodynamic parameters -including maximal and minimal pharmacosensitivity phases -were identified as much as possible from laboratory curves [18] (comparison between treated and untreated tumour growth) or else only estimated on the basis of likeliness after other drug or tissue data when no relevant data were available.…”