RESUMEN
The development of divinylpyrimidine (DVP) reagents for the synthesis of antibody-drug conjugates (ADCs) with in vivo efficacy and tolerability is reported. Detailed structural characterisation of the synthesised ADCs was first conducted followed by in vitro and in vivo evaluation of the ADCs' ability to safely and selectively eradicate target-positive tumours.
Asunto(s)
Antineoplásicos Inmunológicos/farmacología , Inmunoconjugados/química , Indicadores y Reactivos/química , Pirimidinas/química , Animales , Antineoplásicos Inmunológicos/efectos adversos , Línea Celular Tumoral , Humanos , Inmunoconjugados/efectos adversos , Ratones , Prueba de Estudio Conceptual , Trastuzumab/efectos adversos , Trastuzumab/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The metabolic response to endotoxemia closely mimics those seen in sepsis. Here, we show that the urinary excretion of the metabolite 2-hydroxyglutarate (2HG) is dramatically suppressed following lipopolysaccharide (LPS) administration in vivo, and in human septic patients. We further show that enhanced activation of the enzymes responsible for 2-HG degradation, D- and L-2-HGDH, underlie this effect. To determine the role of supplementation with 2HG, we carried out co-administration of LPS and 2HG. This co-administration in mice modulates a number of aspects of physiological responses to LPS, and in particular, protects against LPS-induced hypothermia. Our results identify a novel role for 2HG in endotoxemia pathophysiology, and suggest that this metabolite may be a critical diagnostic and therapeutic target for sepsis.
RESUMEN
PURPOSE: Inherited pathogenic variants in genes encoding the metabolic enzymes succinate dehydrogenase (SDH) and fumarate hydratase predispose to tumor development through accumulation of oncometabolites (succinate and fumarate, respectively; ref. 1). Noninvasive in vivo detection of tumor succinate by proton magnetic resonance spectroscopy (1H-MRS) has been reported in SDH-deficient tumors, but the potential utility of this approach in the management of patients with hereditary leiomyomatosis and renal cell cancer syndrome or Reed syndrome is unknown. EXPERIMENTAL DESIGN: Magnetic resonance spectroscopy (1H-MRS) was performed on three cases and correlated with germline genetic results and tumor IHC when available. RESULTS: Here, we have demonstrated a proof of principle that 1H-MRS can provide a noninvasive diagnosis of hereditary leiomyomatosis and renal cell cancer syndrome or Reed syndrome through detection of fumarate accumulation in vivo. CONCLUSIONS: This study demonstrates that in vivo detection of fumarate could be employed as a functional biomarker.
Asunto(s)
Fumaratos/metabolismo , Mutación de Línea Germinal , Neoplasias Renales/diagnóstico , Leiomiomatosis/diagnóstico , Síndromes Neoplásicos Hereditarios/diagnóstico , Espectroscopía de Protones por Resonancia Magnética/métodos , Neoplasias Cutáneas/diagnóstico , Neoplasias Uterinas/diagnóstico , Adulto , Femenino , Fumarato Hidratasa/genética , Fumarato Hidratasa/metabolismo , Humanos , Neoplasias Renales/metabolismo , Leiomiomatosis/metabolismo , Masculino , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios/metabolismo , Neoplasias Cutáneas/metabolismo , Succinato Deshidrogenasa/genética , Neoplasias Uterinas/metabolismoRESUMEN
RNA methylation is emerging as a regulatory RNA modification that could have important roles in the control and coordination of gene transcription and protein translation. Herein, we describe an in vivo isotope-tracing methodology to demonstrate that the ribonucleoside 5-methylcytidine (m(5)C) is subject to oxidative processing in mammals, forming 5-hydroxymethylcytidine (hm(5)C) and 5-formylcytidine (f(5)C). Furthermore, we have identified hm(5)C in total RNA from all three domains of life and in polyA-enriched RNA fractions from mammalian cells. This suggests m(5)C oxidation is a conserved process that could have critical regulatory functions inside cells.
