RESUMO
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.
Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Acridonas/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Camptotecina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Modelos Biológicos , Proteínas de Neoplasias/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Acridonas/administração & dosagem , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Transporte Biológico , Camptotecina/administração & dosagem , Camptotecina/farmacologia , Sinergismo Farmacológico , Feminino , Células HEK293 , Humanos , Irinotecano , Camundongos , Camundongos SCID , Proteínas de Neoplasias/genética , Transfecção , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The induction profile of endogenous interferons of three types under the action of meglumine acridone acetate and sodium acridone acetate, as well as the characteristics of the kinetics of their accumulation and circulation in the blood of experimental animals are described. Meglumine acridone acetate provided balance in induction, production and circulation of the interferons in the blood vs. sodium aeridone acetate under the same conditions. The optimal dose of meglumine acridone acetate (2.0-3.5 mg/mouse) with effective, consecutive and overlapping induction-production of the interferons ensured their prolonged (for 72 hours) circulation in the blood after a single administration.