RESUMEN
Gefitinib ("Iressa", ZD1839) is an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor, and the single agent is clinically effective in non-small cell lung cancer. Although gefitinib combined with various cytotoxic agents has been reported to enhance cytotoxicity in vitro and in mouse models, the mechanism remains undetermined. Here, to explore the mechanism with topoisomerase I inhibitors, we focused on the efflux pump of the breast cancer resistance protein (BCRP/ABCG2), and then examined whether gefitinib restored drug sensitivity in multidrug-resistant cancer cells overexpressing BCRP. We used PC-6 human small cell lung cancer cells and multidrug-resistant PC-6/SN2-5H cells selected with SN-38 of the active metabolite of irinotecan, and BCRP-overexpressing MCF-7/MX cells selected with mitoxantrone and BCRP cDNA transfectant MCF-7/clone 8 cells. Drug sensitivity against anticancer drugs was determined by tetrazolium dye assay, and intracellular topotecan accumulation by FACScan. The topotecan transport study was done using the plasma membrane vesicles of PC-6/SN2-5H cells. The resistant PC-6/SN2-5H cells overexpressed BCRP but not epidermal growth factor receptor mRNA. Ten micromoles of gefitinib reversed topotecan, SN-38, and mitoxantrone resistance, and increased the intracellular topotecan accumulation in the resistant cells but not in the parental cells. Furthermore, gefitinib inhibited the topotecan transport into the vesicles, and the K(i) value was 1.01 +/- 0.09 micromol/L in the Dixon plot analysis, indicating direct inhibition of BCRP by gefitinib. However, gefitinib was not transported into the vesicles with the high-performance liquid chromatography method. These results indicate that gefitinib reverses BCRP-mediated drug resistance by direct inhibition other than competitive inhibition as a BCRP substrate. Combination of gefitinib and topoisomerase I inhibitors could be clinically effective in cancers expressing BCRP.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/antagonistas & inhibidores , Neoplasias de la Mama/tratamiento farmacológico , Camptotecina/análogos & derivados , Carcinoma de Células Pequeñas/tratamiento farmacológico , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas de Neoplasias/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/biosíntesis , Transportadoras de Casetes de Unión a ATP/metabolismo , Adenosina Trifosfato/metabolismo , Transporte Biológico Activo , Neoplasias de la Mama/metabolismo , Camptotecina/farmacología , Carcinoma de Células Pequeñas/metabolismo , Línea Celular Tumoral , Membrana Celular/metabolismo , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Factor de Crecimiento Epidérmico/biosíntesis , Gefitinib , Humanos , Concentración 50 Inhibidora , Irinotecán , Neoplasias Pulmonares/metabolismo , Mitoxantrona/farmacología , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/metabolismo , Topotecan/farmacocinética , Topotecan/farmacologíaRESUMEN
OBJECTIVE: An entertainment robot was used as occupational therapy instead of animal-assisted therapy to avoid any danger or injury to the patient and maintain cleanliness. This study compared the effectiveness of a robot animal, AIBO, with a toy. METHOD: AIBO is made of metal and responds to spoken commands. We demonstrated AIBO to severely demented elderly people living in a geriatric home and observed their reactions. RESULTS: The most frequent reactions to AIBO consisted of looking at, communicating with, and caring for AIBO. The patients recognized that AIBO was a robot. However, once we dressed AIBO, the patients perceived AIBO as either a dog or a baby. Nevertheless, the presentation of AIBO resulted in positive outcomes for the severe dementia patients, including increased communication between the patients and AIBO. CONCLUSION: AIBO was clearly an effective rehabilitation tool in the treatment of severely demented patients.