title: Optimization of irinotecan chronotherapy with P-glycoprotein inhibition.
abstract: The relevance of P-glycoprotein (P-gp) for irinotecan chronopharmacology was investigated in female B6D2F1 mice. A three-fold 24h 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 (50mg/kg/day i.v.×4days) as a single agent or combined with P-gp inhibitor PSC833 (6.25mg/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 40mg/kg/day×4days) 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.
authors.affiliation: INSERM, U776 "Rythmes biologiques et cancers", CAMPUS CNRS, 7 rue Guy Môquet, F-94801 Villejuif, France; Univ Paris-Sud, UMR-S0776, Orsay F-91405, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Filipski
authors.affiliation: INSERM, U776 "Rythmes biologiques et cancers", CAMPUS CNRS, 7 rue Guy Môquet, F-94801 Villejuif, France; Univ Paris-Sud, UMR-S0776, Orsay F-91405, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Berland
authors.affiliation: INSERM, U776 "Rythmes biologiques et cancers", CAMPUS CNRS, 7 rue Guy Môquet, F-94801 Villejuif, France; Univ Paris-Sud, UMR-S0776, Orsay F-91405, France; Istanbul University Faculty of Pharmacy, Department of Pharmacology, Beyazit TR-34116, Istanbul, Turkey.
authors.forename: Narin
authors.initials: N
authors.lastname: Ozturk
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Unité de Chronothérapie, Département de Cancérologie, Hôpital Paul Brousse, Villejuif F-94807, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Guettier
authors.affiliation: Department of Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
authors.affiliation: INSERM, U776 "Rythmes biologiques et cancers", CAMPUS CNRS, 7 rue Guy Môquet, F-94801 Villejuif, France; Univ Paris-Sud, UMR-S0776, Orsay F-91405, France; Assistance Publique-Hôpitaux de Paris, Unité de Chronothérapie, Département de Cancérologie, Hôpital Paul Brousse, Villejuif F-94807, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Lévi
authors.affiliation: INSERM, U776 "Rythmes biologiques et cancers", CAMPUS CNRS, 7 rue Guy Môquet, F-94801 Villejuif, France; Univ Paris-Sud, UMR-S0776, Orsay F-91405, France; Istanbul University Faculty of Pharmacy, Department of Pharmacology, Beyazit TR-34116, Istanbul, Turkey. Electronic address: aokyar@istanbul.edu.tr.
authors.forename: Alper
authors.initials: A
authors.lastname: Okyar
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019454:Chronotherapy / Q000379:methods*; D002940:Circadian Rhythm / Q000187:drug effects; D003524:Cyclosporins / Q000494:pharmacology*; D023381:Endpoint Determination; D005260:Female; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D000077146:Irinotecan; D051379:Mice; D009092:Mucous Membrane / Q000187:drug effects / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D012333:RNA, Messenger; D000077146:Irinotecan; C507084:Abcb1b protein, mouse; C070272:valspodar; D002166:Camptothecin
keywords: Cancer chronotherapy; Circadian rhythm; Irinotecan; P-glycoprotein; PSC833