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Optimization of irinotecan chronotherapy with P-glycoprotein inhibition
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Filipski, Elisabeth, Berland, Elodie, Ozturk, Narin, Guettier, Catherine, van der Horst, Gijsbertus T. J., Lévi, Francis A. and Okyar, Alper (2014) Optimization of irinotecan chronotherapy with P-glycoprotein inhibition. Toxicology and Applied Pharmacology, 274 (3). pp. 471-479. doi:10.1016/j.taap.2013.12.018 ISSN 0041008X.
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Official URL: http://dx.doi.org/10.1016/j.taap.2013.12.018
Abstract
The relevance of P-glycoprotein (P-gp) for irinotecan chronopharmacology was investigated in female B6D2F1 mice. A three-fold 24 h change in the mRNA expression of Abcb1b was demonstrated in ileum mucosa, with a maximum at Zeitgeber Time (ZT) 15 (p < 0.001). No rhythm was found for abcb1a in ileum mucosa, or for Abcb1a/b in Glasgow osteosarcoma (GOS), a mouse tumor cell line moderately sensitive to irinotecan. Non-tumor-bearing mice received irinotecan (50 mg/kg/day i.v. × 4 days) as a single agent or combined with P-gp inhibitor PSC833 (6.25 mg/kg/day i.p. × 4 days) at ZT3 or ZT15, respectively corresponding to the worst or the best irinotecan tolerability. Endpoints involved survival, body weight change and hematologic toxicity. Antitumor efficacy was studied in GOS-bearing mice receiving irinotecan (25, 30 or 40 mg/kg/day × 4 days) and +/− PSC833 at ZT3 or ZT15, with survival, body weight change, and tumor growth inhibition as endpoints. Non-tumor bearing mice lost an average of 17% or 9% of their body weight according to irinotecan administration at ZT3 or ZT15 respectively (p < 0.001). Dosing at ZT15 rather than ZT3 reduced mean leucopenia (9% vs 53%; p < 0.001). PSC833 aggravated irinotecan lethal toxicity from 4 to ~ 60%. In tumor-bearing mice, body weight loss was ~ halved in the mice on irinotecan or irinotecan–PSC833 combination at ZT15 as compared to ZT3 (p < 0.001). PSC833–irinotecan at ZT15 increased tumor inhibition by ~ 40% as compared to irinotecan only at ZT15. In conclusion, P-gp was an important determinant of the circadian balance between toxicity and efficacy of irinotecan.
| Item Type: | Journal Article | ||||||||||
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| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Journal or Publication Title: | Toxicology and Applied Pharmacology | ||||||||||
| Publisher: | Academic Press | ||||||||||
| ISSN: | 0041008X | ||||||||||
| Official Date: | 1 February 2014 | ||||||||||
| Dates: |
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| Volume: | 274 | ||||||||||
| Number: | 3 | ||||||||||
| Page Range: | pp. 471-479 | ||||||||||
| DOI: | 10.1016/j.taap.2013.12.018 | ||||||||||
| Status: | Peer Reviewed | ||||||||||
| Publication Status: | Published | ||||||||||
| Access rights to Published version: | Restricted or Subscription Access |
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