RESUMEN
Vorinostat [suberoylanilide hydroxamic acid (SAHA)], a histone deacetylase inhibitor, shows limited clinical activity against solid tumors when used alone. The methyl xanthine drug, pentoxifylline (PENT), has been described to have antitumor properties. The aim of this study was to look for the enhanced anticancer activities of both agents when used in combination at doses lower than their respective efficacy dose when used alone. We investigated the antitumor potential of this novel combination in vitro and in vivo. The combination index was assessed for these two drugs to look for synergistic antiproliferative activity against a broad spectrum of human cancer cell lines. Consistent additive to synergistic interactions were observed in HCT116 cells when PENT was combined with SAHA at all drug tested concentrations. The combination of SAHA and PENT induces chromatin condensation and apoptosis downstream of the pan histone deacetylase inhibition and phosphodiesterase regulation, leading to subsequent cell cycle arrest at their lower tested concentrations. Further, the ability of this combination to inhibit angiogenesis, both in vitro and in vivo, was examined and a significant inhibition in tube formation in HUVEC cells and neovascularization of Matrigel plug was observed. A significant inhibition in tumor growth was observed in severe combined immunodeficient mice bearing HCT116 (colon) and PC3 (prostate) human xenografts treated with SAHA (30 mg/kg, intraperitoneal) in combination with PENT (60 mg/kg, intraperitoneal), with no loss in body weight and 100% survival. In conclusion, these findings indicate the enhanced anticancer activity of SAHA in combination with PENT both in vitro and in vivo.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Neoplasias/tratamiento farmacológico , Pentoxifilina/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Sinergismo Farmacológico , Células HCT116 , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/farmacocinética , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/farmacocinética , Células MCF-7 , Masculino , Ratones , Ratones SCID , Neoplasias/irrigación sanguínea , Neoplasias/metabolismo , Neoplasias/patología , Neovascularización Patológica/tratamiento farmacológico , Pentoxifilina/administración & dosificación , Pentoxifilina/farmacocinética , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/farmacocinética , Distribución Aleatoria , Vorinostat , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Herein we report the synthesis and activity of a novel class of HDAC inhibitors based on 2, 3-diphenyl acrylic acid derivatives. The compounds in this series have shown to be potent HDAC inhibitors possessing significant antiproliferative activity. Further compounds in this series were subjected to metabolic stability in human liver microsomes (HLM), mouse liver microsomes (MLM), and exhibits promising stability in both. These efforts culminated with the identification of a developmental candidate (5a), which displayed desirable PK/PD relationships, significant efficacy in the xenograft models and attractive ADME profiles.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Cinamatos/farmacología , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/farmacología , Estilbenos/administración & dosificación , Estilbenos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Administración Oral , Animales , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cinamatos/administración & dosificación , Cinamatos/química , Relación Dosis-Respuesta a Droga , Inhibidores de Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Humanos , Ratones , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Estilbenos/química , Relación Estructura-ActividadRESUMEN
MS-275, a histone deacetylase inhibitor (HDACi), is undergoing clinical trials for treatment of various cancers. Pentoxifylline, a nonselective phosphodiesterase (PDE) inhibitor, has been shown to increase the effectiveness of antitumor chemotherapy. In the present study, the potential anti-cancer activity of MS-275 in combination with pentoxifylline in panel of cell lines and human breast cancer xenograft model were examined. A Panel of cancer cell lines were treated with MS-275 and pentoxifylline to determine their impact on cellular proliferation, cell cycle regulation, apoptosis, anti-angiogenesis. The in vivo activities of MS-275 and pentoxifylline were assessed in a Matrigel plug angiogenesis model and human breast cancer (MDA-MB-231) xenograft model. Combination of MS-275 with pentoxifylline showed enhanced anti-proliferative activity in a panel of cancer cell lines (HCT 116, MCF-7, PC3 and MDA-MB-231). Apoptotic studies performed using, Hoechst staining and cell cycle analysis reveal that this combination at the lower concentrations induces apoptosis downstream of the HDAC inhibition and PDE regulation. Further, combination showed enhanced antiangiogenic activity in Matrigel tube formation assay using HUVECs and in Matrigel plug assay in vivo. A significant inhibition (P<0.001) of tumor growth was observed in mice bearing MDA-MB-231 breast cancer xenograft treated with the combination of MS-275 (5mg/kg p.o.) and pentoxifylline (60 mg/kg i.p.) than treatments alone, without much signs of toxicity. Taken together, our study demonstrated enhanced anticancer activity of MS-275 and pentoxifylline combination both in vitro and in vivo with reduced toxicity. However, further studies are required to understand the mechanism for this combination effect.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Benzamidas/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Pentoxifilina/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Piridinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Células HCT116 , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/enzimología , Humanos , Células MCF-7 , Ratones SCID , Neovascularización Patológica , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Alterations in antiretroviral pharmacokinetics during pregnancy must be understood for the drugs to be used safely and effectively. Present study is an attempt to understand the potential changes in raltegravir plasma and cerebrospinal fluid pharmacokinetics during pregnancy in late pregnant and non-pregnant rats. In vitro plasma protein binding, metabolic stability, intravenous blood-brain barrier (BBB) permeability and oral pharmacokinetic studies were performed. Raltegravir concentrations in different matrices were measured using LC-MS/MS. Raltegravir plasma protein binding remained similar in both groups, whereas, metabolic stability was significantly lower in pregnant rats than the non-pregnant rats liver microsomes. In oral pharmacokinetic study, peak plasma concentrations and systemic exposures were significantly lower (â¼37%) and clearance was significantly higher (â¼61%) in late pregnant rats compared to non-pregnant rats. However, unlike plasma pharmacokinetics, CSF pharmacokinetic profile of raltegravir was similar in both pregnant and non-pregnant rats. Following intravenous administration, raltegravir showed higher BBB permeability in pregnant rats compared to non-pregnant rats. But the mean CSF-to-plasma ratio was significantly higher in pregnant rats compared to non-pregnant rats suggesting higher brain penetration in pregnant rats. In conclusion, pregnancy significantly affected the plasma pharmacokinetics, whereas cerebrospinal fluid pharmacokinetics remained fairly similar in pregnant and non-pregnant rats. Although current plasma pharmacokinetic data is in contradiction to the reported human data, pregnancy-specific pharmacokinetic changes observed in the current study emphasize the need for close therapeutic monitoring while treating the pregnant population and also warrants the need for additional clinical data with larger group of patients.