RESUMEN
BACKGROUND: Gemcitabine is used to treat a wide range of tumours, but its efficacy is limited by cancer cell resistance mechanisms. NUC-1031, a phosphoramidate modification of gemcitabine, is the first anti-cancer ProTide to enter the clinic and is designed to overcome these key resistance mechanisms. METHODS: Sixty-eight patients with advanced solid tumours who had relapsed after treatment with standard therapy were recruited to a dose escalation study to determine the recommended Phase II dose (RP2D) and assess the safety of NUC-1031. Pharmacokinetics and anti-tumour activity was also assessed. RESULTS: Sixty-eight patients received treatment, 50% of whom had prior exposure to gemcitabine. NUC-1031 was well tolerated with the most common Grade 3/4 adverse events of neutropaenia, lymphopaenia and fatigue occurring in 13 patients each (19%). In 49 response-evaluable patients, 5 (10%) achieved a partial response and 33 (67%) had stable disease, resulting in a 78% disease control rate. Cmax levels of the active intracellular metabolite, dFdCTP, were 217-times greater than those reported for equimolar doses of gemcitabine, with minimal toxic metabolite accumulation. The RP2D was determined as 825 mg/m2 on days 1, 8 and 15 of a 28-day cycle. CONCLUSIONS: NUC-1031 was well tolerated and demonstrated clinically significant anti-tumour activity, even in patients with prior gemcitabine exposure and in cancers not traditionally perceived as gemcitabine-responsive.
Asunto(s)
Antineoplásicos/administración & dosificación , Citidina Monofosfato/análogos & derivados , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Citidina Monofosfato/administración & dosificación , Citidina Monofosfato/efectos adversos , Citidina Monofosfato/farmacocinética , Esquema de Medicación , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Recurrencia , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
The 18â kDa translocator protein (TSPO) is a ubiquitous conserved outer mitochondrial membrane protein implicated in numerous cell and tissue functions, including steroid hormone biosynthesis, respiration, cell proliferation, and apoptosis. TSPO binds with high affinity to cholesterol and numerous compounds, is expressed at high levels in steroid-synthesizing tissues, and mediates cholesterol import into mitochondria, which is the rate-limiting step in steroid formation. In humans, the rs6971 polymorphism on the TSPO gene leads to an amino acid substitution in the fifth transmembrane loop of the protein, which is where the cholesterol-binding domain of TSPO is located, and this polymorphism has been associated with anxiety-related disorders. However, recent knockout mouse models have provided inconsistent conclusions of whether TSPO is directly involved in steroid synthesis. In this report, we show that TSPO deletion mutations in rat and its corresponding rs6971 polymorphism in humans alter adrenocorticotropic hormone-induced plasma corticosteroid concentrations. Rat tissues examined show increased cholesteryl ester accumulation, and neurosteroid formation was undetectable in homozygous rats. These results also support a role for TSPO ligands in diseases with steroid-dependent stress and anxiety elements.
Asunto(s)
Hormona Adrenocorticotrópica/farmacología , Proteínas Portadoras/genética , Hidrocortisona/sangre , Polimorfismo de Nucleótido Simple , Receptores de GABA-A/genética , Receptores de GABA/genética , Adolescente , Adulto , Animales , Secuencia de Bases , Proteínas Portadoras/metabolismo , Ésteres del Colesterol/biosíntesis , Ésteres del Colesterol/sangre , Gonadotropina Coriónica/farmacología , Clonación Molecular , Corticosterona/biosíntesis , Corticosterona/sangre , Embrión de Mamíferos , Escherichia coli/genética , Escherichia coli/metabolismo , Expresión Génica , Humanos , Hidrocortisona/biosíntesis , Masculino , Plásmidos/química , Plásmidos/metabolismo , Pregnanolona/biosíntesis , Pregnanolona/sangre , Ratas , Ratas Transgénicas , Receptores de GABA/metabolismo , Receptores de GABA-A/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Testosterona/biosíntesis , Testosterona/sangre , Dedos de Zinc , Cigoto/efectos de los fármacos , Cigoto/crecimiento & desarrollo , Cigoto/metabolismoRESUMEN
BACKGROUND: The prognosis of patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) is variable, despite a myriad of prognostic markers. We compared and integrated the established prognostic models, HAP and ART scores, for their accuracy of overall survival (OS) prediction. RESULTS: In both training and validation sets, HAP and ART scores emerged as independent predictors of OS (p<0.01) with HAP achieving better prognostic accuracy (c-index: 0.68) over ART (0.57). We tested both scores in combination to evaluate their combined ability to predict OS. Subgroup analysis of BCLC-C patients revealed favorable HAP stage (p<0.001) and radiological response after initial TACE (p<0.001) as positive prognostic factors. PATIENTS AND METHODS: Prognostic scores were studied using multivariable Cox regression and c-index analysis in 83 subjects with Barcelona Clinic Liver Cancer (BCLC) A/B stage from UK and Italy (training set), and 660 from Korea and Japan (validation set), all treated with conventional TACE. Scores were further validated in an separate analysis of patients with BCLC-C stage disease (n=63) receiving initial TACE. CONCLUSION: ART and HAP scores are validated indices in patients with intermediate stage HCC undergoing TACE. The HAP score is best suited for screening patients prior to initial TACE, whilst sequential ART assessment improves early detection of chemoembolization failure. BCLC-C patients with low HAP stage may be a subgroup where TACE should be explored in clinical studies.