title: Quantitative evaluation of the combination between cytotoxic drug and efflux transporter inhibitors based on a tumour growth inhibition model.
abstract: ATP-Binding Cassette transporters such as ABCG2 confer resistance to various anticancer drugs including irinotecan and its active metabolite, SN38. Early quantitative evaluation of efflux transporter inhibitors-cytotoxic combination requires quantitative drug-disease models. A proof-of-concept study has been carried out for studying the effect of a new ABCG2 transporter inhibitor, MBLI87 combined to irinotecan in mice xenografted with cells overexpressing ABCG2. Mice were treated with irinotecan alone or combined to MBLI87, and tumour size was periodically measured. To model those data, a tumour growth inhibition model was developed. Unperturbed tumour growth was modelled using Simeoni's model. Drug effect kinetics was accounted for by a Kinetic-Pharmacodynamic approach. Effect of inhibitor was described with a pharmacodynamic interaction model where inhibitor enhances activity of cytotoxic. This model correctly predicted tumour growth dynamics from our study. MBLI87 increased irinotecan potency by 20% per μmol of MBLI87. This model retains enough complexity to simultaneously describe tumour growth and effect of this type of drug combination. It can thus be used as a template to early evaluate efflux transporter inhibitors in-vivo.
authors: EMR3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Oullins, France; Université de Lyon, Lyon, France.
authors: Alexandre
authors: A
authors: Sostelly
authors: Léa
authors: L
authors: Payen
authors: Jérôme
authors: J
authors: Guitton
authors: Attilio
authors: A
authors: Di Pietro
authors: Pierre
authors: P
authors: Falson
authors: Mylène
authors: M
authors: Honorat
authors: Ahcène
authors: A
authors: Boumendjel
authors: Annabelle
authors: A
authors: Gèze
authors: Gilles
authors: G
authors: Freyer
authors: Michel
authors: M
authors: Tod
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D054831:Acridones / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D001692:Biological Transport; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C559426:9-oxo-9,10-dihydroacridine-4-carboxylic acid 3,4-dimethoxyphenethyl amide; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D054831:Acridones; D000972:Antineoplastic Agents, Phytogenic; D009363:Neoplasm Proteins; D000077146:Irinotecan; D002166:Camptothecin
keywords: ABC transporters; Anticancer drug resistance; NONMEM; Tumor growth modelling