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1.
Int J Mol Sci ; 21(8)2020 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-32295203

RESUMEN

(1) Background: RX-3117 (fluorocyclopentenyl-cytosine) is a cytidine analog that inhibits DNA methyltransferase 1 (DNMT1). We investigated the mechanism and potential of RX-3117 as a demethylating agent in several in vitro models. (2) Methods: we used western blotting to measure expression of several proteins known to be down-regulated by DNA methylation: O6-methylguanine-DNA methyltransferase (MGMT) and the tumor-suppressor genes, p16 and E-cadherin. Transport of methotrexate (MTX) mediated by the proton-coupled folate transporter (PCFT) was used as a functional assay. (3) Results: RX-3117 treatment decreased total DNA-cytosine-methylation in A549 non-small cell lung cancer (NSCLC) cells, and induced protein expression of MGMT, p16 and E-cadherin in A549 and SW1573 NSCLC cells. Leukemic CCRF-CEM cells and the MTX-resistant variant (CEM/MTX, with a deficient reduced folate carrier) have a very low expression of PCFT due to promoter hypermethylation. In CEM/MTX cells, pre-treatment with RX-3117 increased PCFT-mediated MTX uptake 8-fold, and in CEM cells 4-fold. With the reference hypomethylating agent 5-aza-2'-deoxycytidine similar values were obtained. RX-3117 also increased PCFT gene expression and PCFT protein. (4) Conclusion: RX-3117 down-regulates DNMT1, leading to hypomethylation of DNA. From the increased protein expression of tumor-suppressor genes and functional activation of PCFT, we concluded that RX-3117 might have induced hypomethylation of the promotor.


Asunto(s)
Citidina/análogos & derivados , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Transportador de Folato Acoplado a Protón/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Línea Celular Tumoral , Citidina/farmacología , ADN (Citosina-5-)-Metiltransferasa 1/genética , Metilación de ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Metotrexato/farmacología , Transportador de Folato Acoplado a Protón/genética , Proteínas Supresoras de Tumor/genética
2.
Expert Opin Investig Drugs ; 28(4): 311-322, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30879349

RESUMEN

INTRODUCTION: RX-3117 is an oral, small molecule cytidine analog anticancer agent with an improved pharmacological profile relative to gemcitabine and other nucleoside analogs. The agent has excellent activity against various cancer cell lines and xenografts including gemcitabine-resistant variants and it has excellent oral bioavailability; it is not a substrate for the degradation enzyme cytidine deaminase. RX-3117 is being evaluated at a daily oral schedule of 700 mg (5 days/week for 3 weeks) which results in plasma levels in the micromolar range that have been shown to be cytotoxic to cancer cells. It has shown clinical activity in refractory bladder cancer and pancreatic cancer. Areas covered: The review provides an overview of the relevant market and describes the mechanism of action, main pharmacokinetic/pharmacodynamic features and clinical development of this investigational small molecule. Expert opinion: RX-3117 is selectively activated by uridine-cytidine kinase 2 (UCK2), which is expressed only in tumors and has a dual mechanism of action: DNA damage and inhibition of DNA methyltransferase 1 (DNMT1). Because of its tumor selective activation, novel mechanism of action, excellent oral bioavailability and candidate biomarkers for patient selection, RX-3117 has the potential to replace gemcitabine in the treatment of a spectrum of cancer types.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Citidina/análogos & derivados , Neoplasias/tratamiento farmacológico , Administración Oral , Antimetabolitos Antineoplásicos/farmacocinética , Antimetabolitos Antineoplásicos/farmacología , Disponibilidad Biológica , Citidina/farmacocinética , Citidina/farmacología , Citidina/uso terapéutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Humanos , Neoplasias/patología , Selección de Paciente , Gemcitabina
3.
Nucleosides Nucleotides Nucleic Acids ; 35(10-12): 619-630, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27906620

RESUMEN

RX-3117 (fluorocyclopentenyl-cytosine) is a novel cytidine analog currently being evaluated in a Phase Ib clinical trial in cancer patients with solid tumors. The radiosensitizing effect of RX-3117 was studied in A2780 ovarian cancer cells and non-small cell lung cancer cell lines and related to cell survival and the effect on cell cycle and cell cycle proteins. RX-3117 has a schedule-dependent radiosensitizing effect, but only at pre-incubation (dose modifying factors: 1.4-1.8), observed at pulse and fractionated irradiation. Radiosensitizion was also seen in a three-dimensional spheroid model. At the low radiosensitizing concentration, RX-3117 in combination with radiation led to an accumulation of cells in S-phase, which was accompanied with an increase of cell cycle proteins such as p-Chk2 and p-cdc25C. In addition, RX-3117 caused DNA damage and increased apoptosis. In conclusion, our in vitro experiments showed a radiosensitizing effect of RX-3117.


Asunto(s)
Citidina/análogos & derivados , Fármacos Sensibilizantes a Radiaciones/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Citidina/farmacología , Daño del ADN , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Neoplasias Pulmonares , Neoplasias Ováricas
4.
PLoS One ; 11(9): e0162901, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27612203

RESUMEN

Fluorocyclopentenylcytosine (RX-3117) is an orally available cytidine analog, currently in Phase I clinical trial. RX-3117 has promising antitumor activity in various human tumor xenografts including gemcitabine resistant tumors. RX-3117 is activated by uridine-cytidine kinase (UCK). Since UCK exists in two forms, UCK1 and UCK2, we investigated which form is responsible for RX-3117 phosphorylation. For that purpose we transfected A549 and SW1573 cell lines with UCK-siRNAs. Transfection of UCK1-siRNA efficiently downregulated UCK1-mRNA, but not UCK2-mRNA expression, and did not affect sensitivity to RX-3117. However, transfection of UCK2-siRNA completely downregulated UCK2-mRNA and protein and protected both A549 and SW1573 against RX-3117. UCK enzyme activity in two panels of tumor cell lines and xenograft cells correlated only with UCK2-mRNA expression (r = 0.803 and 0.915, respectively), but not with UCK1-mRNA. Moreover, accumulation of RX-3117 nucleotides correlated with UCK2 expression. In conclusion, RX-3117 is activated by UCK2 which may be used to select patients potentially sensitive to RX-3117.


Asunto(s)
Citidina/análogos & derivados , Uridina Quinasa/metabolismo , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Citidina/química , Citidina/farmacología , Regulación hacia Abajo/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Fosforilación/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Análisis de Regresión , Reproducibilidad de los Resultados , Especificidad por Sustrato/efectos de los fármacos , Transfección , Uridina Quinasa/genética
5.
Pharmacol Biochem Behav ; 93(2): 112-20, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19394358

RESUMEN

Clavulanic acid is a member of the beta lactam family of antibiotics with little or no intrinsic antibacterial activity of its own; instead, it is used to enhance the activity of antibiotics by blocking bacterial beta-lactamases. Because clavulanic acid by itself is very safe, orally active and shows good brain penetrance, we sought to determine if it had any potential as a psychotherapeutic. Clavulanic acid was a tested across three mammalian species, hamsters, rats and cotton-top tamarin monkeys in a series of behavioral assays designed to screen for anxiolytic activity. In addition, several studies were done in rodents to compare the behavioral profile of clavulanic acid to the commonly prescribed benzodiazepines, particularly with respect to their unwanted side effects of motor depression, amnesia and neuroendocrine dysregulation. Our findings show that clavulanic acid is a highly potent anxiolytic in rodents without altering motor activity in the open field test, normal learning and memory in the Morris water maze, or normal stress hormone release. Orally administered clavulanic acid significantly reduces measures of anxiety in male/female pairs of cotton-top tamarins. In addition, male tamarins showed a highly significant increase in sexual arousal as measured by the number of penile erections. The fact clavulanic acid has anxiolytic activity in the tamarin holds the promise that this drug may be an effective therapeutic for the treatment of anxiety disorders in humans.


Asunto(s)
Ansiolíticos , Ácido Clavulánico/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores de beta-Lactamasas , Animales , Clordiazepóxido/farmacología , Ácido Clavulánico/efectos adversos , Cricetinae , Inhibidores Enzimáticos/efectos adversos , Aprendizaje/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Mesocricetus , Actividad Motora/efectos de los fármacos , Sistemas Neurosecretores/efectos de los fármacos , Erección Peniana/efectos de los fármacos , Ratas , Ratas Wistar , Saguinus , Estrés Psicológico/fisiopatología , Estrés Psicológico/prevención & control
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