RESUMEN
Laquinimod is an oral drug currently being evaluated for the treatment of relapsing, remitting, and primary progressive multiple sclerosis and Huntington's disease. Laquinimod exerts beneficial activities on both the peripheral immune system and the CNS with distinctive changes in CNS resident cell populations, especially astrocytes and microglia. Analysis of genome-wide expression data revealed activation of the aryl hydrocarbon receptor (AhR) pathway in laquinimod-treated mice. The AhR pathway modulates the differentiation and function of several cell populations, many of which play an important role in neuroinflammation. We therefore tested the consequences of AhR activation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) using AhR knockout mice. We demonstrate that the pronounced effect of laquinimod on clinical score, CNS inflammation, and demyelination in EAE was abolished in AhR-/- mice. Furthermore, using bone marrow chimeras we show that deletion of AhR in the immune system fully abrogates, whereas deletion within the CNS partially abrogates the effect of laquinimod in EAE. These data strongly support the idea that AhR is necessary for the efficacy of laquinimod in EAE and that laquinimod may represent a first-in-class drug targeting AhR for the treatment of multiple sclerosis and other neurodegenerative diseases.
Asunto(s)
Encefalomielitis Autoinmune Experimental/etiología , Encefalomielitis Autoinmune Experimental/metabolismo , Quinolonas/farmacología , Receptores de Hidrocarburo de Aril/agonistas , Receptores de Hidrocarburo de Aril/metabolismo , Animales , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/patología , Femenino , Eliminación de Gen , Expresión Génica , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Ratones , Ratones Noqueados , Receptores de Hidrocarburo de Aril/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo , TranscriptomaRESUMEN
RX-3117 (fluorocyclopentenylcytosine) is a cytidine analog and this class of drugs, including gemcitabine, has been widely used for the treatment of various types of cancers. However, there is no oral formulation of gemcitabine and drug resistance to gemcitabine is common. In this study, the efficacy of orally-administered RX-3117 was examined in 9 different human tumor xenograft models (colon, non-small cell lung, small cell lung, pancreatic, renal and cervical), grown subcutaneously in athymic nude mice. In the Colo 205, H460, H69 and CaSki models, gemcitabine treatment resulted in 28%, 30%, 25% and 0% tumor growth inhibition (TGI), respectively, whereas oral treatment with RX-3117 induced 100%, 78%, 62% and 66% TGI, respectively. This indicates that RX-3117 may have the potential to be used for the treatment of tumors that do not respond to gemcitabine. RX-3117 was also evaluated in a single primary low-passage human pancreatic Tumorgraft™CTG-0298 (TGI 76%), which is relatively resistant to gemcitabine (TGI 38%) and has a favorable RX-3117-activating enzyme profile. These studies demonstrated the therapeutic potential and anticancer efficacy of RX-3117.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Citidina/análogos & derivados , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos , Neoplasias/tratamiento farmacológico , Administración Oral , Animales , Línea Celular Tumoral , Citidina/administración & dosificación , Citidina/uso terapéutico , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Modelos Animales de Enfermedad , Femenino , Células HCT116 , Células HT29 , Humanos , Ratones , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
Pre-clinical studies of multidrug resistance (MDR) usually address severe resistance, yet moderate MDR is already clinically-impeding. The purpose of this study was to characterize moderate drug resistance in human colon cancer, and it's modulation by fluoxetine. In vitro fluoxetine enhanced doxorubicin's cytotoxicity (10-fold), increased doxorubicin's intracellular accumulation (32%) and decreased efflux of intracellular doxorubicin (70%). In vivo, mild treatment with a doxorubicin-fluoxetine combination slowed-down tumor progression significantly (p<0.001 vs. doxorubicin alone), comparable to aggressive treatment with bevacizumab. Collectively, our results suggest that combinations of fluoxetine with chemotherapeutic drugs (P-glycoprotein substrates) are worthy of further pursuit for moderate MDR in the clinic.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Resistencia a Antineoplásicos , Fluoxetina/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Bevacizumab , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Doxorrubicina/administración & dosificación , Resistencia a Múltiples Medicamentos , Femenino , Citometría de Flujo , Humanos , Ratones , Ratones Desnudos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Proteínas de Neoplasias/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of N-hydroxy-3-phenyl-2-propenamides were prepared as novel inhibitors of human histone deacetylase (HDAC). These compounds were potent enzyme inhibitors, having IC(50)s < 400 nM in a partially purified enzyme assay. However, potency in cell growth inhibition assays ranged over 2 orders of magnitude in two human carcinoma cell lines. Selected compounds having cellular IC(50) < 750 nM were tested for maximum tolerated dose (MTD) and for efficacy in the HCT116 human colon tumor xenograft assay. Four compounds having an MTD > or = 100 mg/kg were selected for dose-response studies in the HCT116 xenograft model. One compound, 9 (NVP-LAQ824), had significant dose-related activity in the HCT116 colon and A549 lung tumor models, high MTD, and low gross toxicity. On the basis, in part, of these properties, 9 has entered human clinical trials in 2002.