RESUMEN
To evaluate the effect and mechanism of radiotherapy (RT)-sorafenib pharmacokinetics (PK) in different regimens with conventional or high dose irradiation. Between February 2012 and December 2018, 43 patients with portal vein tumor thrombosis treated with sorafenib plus conventional RT (58%) or stereotactic body radiation therapy (SBRT, 42%) were retrospectively reviewed. In vivo and in vitro studies of concurrent and sequential RT with sorafenib were designed. SBRT resulted in a 3-fold increase in complete recanalization compared to conventional RT group (28% vs. 8%, p = 0.014). Compared to the control group, the area under the concentration vs. time curve (AUC) of sorafenib was increased in the concurrent RT2Gy and RT9Gy groups and the sequential RT9Gy group by 132% (p = 0.046), 163% (p = 0.038) and 102% (p = 0.018), respectively; and was decreased by 59% in the sequential RT2Gy group (p = 0.036). Sequential RT2Gy and RT9Gy increased CYP3A4 activity by 82% (p = 0.028) and 203% (p = 0.0004), respectively, compared to that with the corresponding concurrent regimen. SBRT produced better recanalization than conventional RT with sorafenib. The AUC of sorafenib was modulated by RT. P-gp expression was not influenced by RT. The sequential RT regimen increased CYP3A4 activity that may increase the RT-sorafenib synergy effect and overall sorafenib activity. The biodistribution of sorafenib was modulated by local RT with the different regimens.
Asunto(s)
Antineoplásicos/farmacocinética , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Vena Porta/efectos de la radiación , Inhibidores de Proteínas Quinasas/farmacocinética , Radiocirugia/métodos , Sorafenib/farmacocinética , Trombosis de la Vena/radioterapia , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/efectos de la radiación , Animales , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/complicaciones , Línea Celular Tumoral , Terapia Combinada , Ciclosporina/farmacología , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/farmacología , Relación Dosis-Respuesta en la Radiación , Inducción Enzimática/efectos de la radiación , Humanos , Neoplasias Hepáticas/complicaciones , Masculino , FN-kappa B/metabolismo , FN-kappa B/efectos de la radiación , Inhibidores de Proteínas Quinasas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Estudios Retrospectivos , Sorafenib/uso terapéutico , Organismos Libres de Patógenos Específicos , Distribución Tisular , Trombosis de la Vena/etiologíaRESUMEN
The mdr1b gene is thought to be a "stress-responsive" gene, however it is unknown if this gene is regulated by p53 in the whole animal. Moreover, it is unknown if overexpression of mdr1b affects cell survival. The dependence of mdr1b upon p53 for upregulation was evaluated in p53 knockout mice. Wild-type (wt) or p53-/- mice were treated singly or in combination with gamma irradiation (IR) and/or the potent DNA damaging agent, diethylnitrosoamine (DEN). Both IR and DEN induced mdr1b in wild-type animals, but not in the p53-/- mice. IR also upregulated endogenous mdr1b in the H35 liver cell line, and the mdr1b promoter was activated by IR and activation correlated with p53 levels; moreover activation required an intact p53 binding site. Colony survival studies revealed that co-transfection of both mdr1b and p53 dramatically reduced colony numbers compared to cells transfected with either p53 or mdr1b alone and cells microinjected with both mdr1b and p53 had a more dramatic loss in viability compared to cells injected with either expression vector alone. Further studies using acridine orange and ethidium bromide to measure apoptosis revealed that mdr1b caused apoptosis and this was enhanced by p53, however the increased apoptosis required a functional p53 transactivation domain. These studies indicate that mdr1b is a downstream target of p53 in the whole animal and expression of mdr1b facilitates p53-mediated cell death.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/efectos de la radiación , Alquilantes/farmacología , Animales , Secuencia de Bases , Sitios de Unión , Muerte Celular/fisiología , Células Cultivadas , Secuencia Conservada , Daño del ADN/efectos de los fármacos , Daño del ADN/genética , Dietilnitrosamina/farmacología , Rayos gamma , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/efectos de la radiación , Masculino , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Regiones Promotoras Genéticas , Radiación Ionizante , Ratas , Homología de Secuencia de Ácido Nucleico , Proteína p53 Supresora de Tumor/genética , Regulación hacia Arriba , Irradiación Corporal Total , Miembro 4 de la Subfamilia B de Casete de Unión a ATPRESUMEN
Failure of chemotherapy is frequently observed in patients previously treated with radiotherapy. To establish a cellular model for examining this resistance phenotype a series of mammalian tumor cell lines were exposed in vitro to fractionated X-irradiation and were then shown to express resistance to multiple antitumor drugs, including vincristine, etoposide and cisplatin. In these experiments the radiation was delivered as 10 fractions of 5 Gy (dose resulting in 1 log cell kill) given intermittently over several months. We now report that a comparable multidrug-resistance profile is expressed by human SK-OV-3 human ovarian tumor cells exposed in vitro to low dose (2 Gy) twice-daily fractions of X-rays given for 5 days on two consecutive weeks, essentially mimicking clinical practice, involving an overexpression of two MDR-associated proteins, P-glycoprotein and the multidrug resistance protein 1 (MRP1), with the latter being readily detectable by immunocytochemistry.