Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
Más filtros

Banco de datos
Tipo del documento
País de afiliación
Intervalo de año de publicación
1.
JOP ; 12(2): 123-5, 2011 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-21386636
2.
Pharmacogenet Genomics ; 20(10): 638-41, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20729791

RESUMEN

High interindividual pharmacokinetic variability was observed in phase 1 studies of vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase inhibitor. Thus, we hypothesized that the variability can be explained by genetic variants of the uridine 5'-diphosphate-glucuronosyltransferases (UGTs) involved in vorinostat metabolism. Baculosomes expressing human UGTs and 52 human liver microsomes were screened for vorinostat glucuronidation activity to identify the potential enzymes and functional variants. UGT2B17 had the largest activity. Human liver microsomes with at least one copy of UGT2B17 showed significantly greater enzymatic activity than those with UGT2B17 null genotype (P<0.004). UGT2B17 plays an important role in vorinostat hepatic glucuronidation and the gene deletion polymorphism may influence vorinostat biotransformation and clearance. The clinical impact of this UGT2B17 genetic variant on vorinostat metabolism and drug effect is unknown.


Asunto(s)
Glucurónidos/genética , Glucurónidos/metabolismo , Ácidos Hidroxámicos/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Genotipo , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Glicosilación/efectos de los fármacos , Humanos , Cinética , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Farmacogenética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de Regresión , Especificidad por Sustrato/efectos de los fármacos , Vorinostat
3.
JOP ; 11(4): 334-5, 2010 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-20601806

RESUMEN

Diabetes mellitus and its related factors such as hyperinsulinemia have been linked to various cancer risks and outcomes. Previous research has offered inconsistent results in terms of relationship between diabetes and pancreatic cancers. Establishing clear association between these two entities may guide us in improving clinical outcomes of pancreatic cancer patients. Two abstracts that examined the association between diabetes mellitus and pancreatic cancer are updated in this paper. Herein, the authors report updated information from the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting in association between pancreatic cancer and diabetes mellitus. The present paper illustrates insufficient knowledge base to draw a conclusion in this topic. However, validation and understanding of the association could have significant clinical implications with respect to cancer prevention, early detection, and treatment. As such, further investigations are warranted to explore the link diabetes and pancreatic cancers.


Asunto(s)
Carcinoma/terapia , Complicaciones de la Diabetes/terapia , Neoplasias Pancreáticas/terapia , Carcinoma/complicaciones , Carcinoma/diagnóstico , Chicago , Congresos como Asunto , Complicaciones de la Diabetes/diagnóstico , Humanos , Oncología Médica/métodos , Oncología Médica/tendencias , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/diagnóstico , Pronóstico , Sociedades Médicas/organización & administración , Resultado del Tratamiento , Estados Unidos
4.
Mol Cancer Ther ; 19(6): 1298-1307, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32229606

RESUMEN

The programmed cell death 1 (PD-1) pathway represents a major immune checkpoint, which may be engaged by cells in the tumor microenvironment to overcome active T-cell immune surveillance. Pembrolizumab (Keytruda®, MK-3475) is a potent and highly selective humanized mAb of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances the functional activity of T cells to facilitate tumor regression and ultimately immune rejection. Pembrolizumab binds to human and cynomolgus monkey PD-1 with picomolar affinity and blocks the binding of human and cynomolgus monkey PD-1 to PD-L1 and PD-L2 with comparable potency. Pembrolizumab binds both the C'D and FG loops of PD-1. Pembrolizumab overcomes human and cynomolgus monkey PD-L1-mediated immune suppression in T-cell cultures by enhancing IL2 production following staphylococcal enterotoxin B stimulation of healthy donor and cancer patient cells, and IFNγ production in human primary tumor histoculture. Ex vivo and in vitro studies with human and primate T cells show that pembrolizumab enhances antigen-specific T-cell IFNγ and IL2 production. Pembrolizumab does not mediate FcR or complement-driven effector function against PD-1-expressing cells. Pembrolizumab displays dose-dependent clearance and half-life in cynomolgus monkey pharmacokinetic and toxicokinetic studies typical for human IgG4 antibodies. In nonhuman primate toxicology studies, no findings of toxicologic significance were observed. The preclinical data for pembrolizumab are consistent with the clinical anticancer activity and safety that has been demonstrated in human clinical trials.


Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/farmacocinética , Leucocitos Mononucleares/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Linfocitos T/efectos de los fármacos , Animales , Antineoplásicos Inmunológicos/farmacocinética , Antineoplásicos Inmunológicos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacocinética , Inhibidores de Puntos de Control Inmunológico/farmacología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/patología , Macaca fascicularis , Ratones , Ratones Endogámicos BALB C , Neoplasias/inmunología , Neoplasias/patología , Proteína 2 Ligando de Muerte Celular Programada 1/antagonistas & inhibidores , Proteína 2 Ligando de Muerte Celular Programada 1/inmunología , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/inmunología , Linfocitos T/inmunología , Linfocitos T/patología , Distribución Tisular , Pruebas de Toxicidad
5.
Pharmacogenomics J ; 9(4): 283-90, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19381162

RESUMEN

We have studied the global frequency distributions of 10 single nucleotide polymorphisms (SNPs) across 132 kb of CYP2C8 and CYP2C9 in approximately 2500 individuals representing 45 populations. Five of the SNPs were in noncoding sequences; the other five involved the more common missense variants (four in CYP2C8, one in CYP2C9) that change amino acids in the gene products. One haplotype containing two CYP2C8 coding variants and one CYP2C9 coding variant reaches an average frequency of 10% in Europe; a set of haplotypes with a different CYP2C8 coding variant reaches 17% in Africa. In both cases these haplotypes are found in other regions of the world at <1%. This considerable geographic variation in haplotype frequencies impacts the interpretation of CYP2C8/CYP2C9 association studies, and has pharmacogenomic implications for drug interactions.


Asunto(s)
Hidrocarburo de Aril Hidroxilasas/genética , África , Asia , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP2C9 , Europa (Continente) , Frecuencia de los Genes , Genética de Población , Haplotipos , Humanos , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple
6.
Int J Biol Markers ; 24(1): 1-10, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19404916

RESUMEN

The detection of circulating tumor cells (CTCs) in peripheral blood may have important prognostic and predictive implications in breast cancer treatment. A limitation in this field has been the lack of a validated method of accurately measuring CTCs. While sensitivity has improved using RT-PCR, specificity remains a major challenge. The goal of this paper is to present a sensitive and specific methodology of detecting CTCs in women with HER-2 positive metastatic breast cancer, and to examine its role as a marker that tracks disease response during treatment with trastuzumab-containing regimens. The study included patients with HER-2-positive metastatic breast cancer enrolled on two different clinical protocols using a trastuzumab-containing regimen. Serial CTCs were measured at planned time points and clinical correlations were made. Immunomagnetic selection of circulating epithelial cells was used to address the specificity of tumor cell detection using cytokeratin 19 (CK19). In addition, the extracellular domain of the HER-2 protein (HER-2/ECD) was measured to determine if CTCs detected by CK19 accurately reflect tumor burden. The presence of CTCs at first restaging was associated with disease progression. We observed an association between CK19 and HER-2/ECD. The association of HER-2/ECD with clinical response followed a similar pattern to that seen with CK19. Finally, the absence of HER-2/ECD at best overall response and a change of HER-2/ECD from positive at baseline to negative at best overall response was associated with favorable treatment response. Our study supports the prognostic and predictive role of the detection of CTCs in treatment of HER-2-positive metastatic breast cancer patients. The association between CK19 and markers of disease burden is in line with the concept that CTCs may be a reliable measure of tumor cells in the peripheral blood of patients with metastatic breast cancer. The association of CTCs at first restaging with treatment failure indicates that CTCs may have a role as surrogate markers to monitor treatment response.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/secundario , Células Neoplásicas Circulantes/metabolismo , Receptor ErbB-2/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/uso terapéutico , Secuencia de Bases , Biomarcadores de Tumor/química , Biomarcadores de Tumor/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Cartilla de ADN/genética , Femenino , Flavonoides/uso terapéutico , Humanos , Separación Inmunomagnética/métodos , Separación Inmunomagnética/estadística & datos numéricos , Queratina-19/genética , Queratina-19/metabolismo , Piperidinas/uso terapéutico , Pronóstico , Estructura Terciaria de Proteína , Receptor ErbB-2/química , Sensibilidad y Especificidad , Trastuzumab , Vinblastina/análogos & derivados , Vinblastina/uso terapéutico , Vinorelbina
7.
World J Gastroenterol ; 14(10): 1622-4, 2008 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-18330959

RESUMEN

We report a case of pseudocirrhosis arising in the setting of regression of liver metastases from pancreatic cancer. A 55-year-old asymptomatic woman presented to our clinic with newly diagnosed metastatic pancreatic cancer with extensive liver metastases. She underwent systemic chemotherapy with gemcitabine and oxaliplatin (GEMOX). After 8 cycles of therapy, she had a remarkable response to the therapy evidenced by decline of carcinoembryonic antigen (CEA) and CA19 by > 50% and nearly complete resolution of hepatic metastases in computed tomography (CT) scan. Shortly after, she developed increasing bilateral ankle edema and ascites, associated with dyspnea, progressive weight gain, and declining performance status. Gemcitabine and oxaliplatin were discontinued as other causes of her symptoms such as congestive heart disease or venous thrombosis were ruled out. CT scan 6 mo after the initiation of GEMOX revealed worsening ascites with a stable pancreatic mass. However, it also revealed a lobular hepatic contour, segmental atrophy, and capsular retraction mimicking the appearance of cirrhosis. She was managed with aggressive diuresis and albumin infusions which eventually resulted in a resolution of the above-mentioned symptoms as well as complete resolution of pseudocirrhotic appearance of the liver and ascites in CT scan. This case demonstrates that pancreatic cancer patients can develop pseudocirrhosis. Clinicians and radiologist should be well aware of this entity as early recognition and management can lead to a near complete recovery of liver function and much improved quality of life as illustrated in this case.


Asunto(s)
Cirrosis Hepática/diagnóstico , Cirrosis Hepática/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Pancreáticas/patología , Albúminas/uso terapéutico , Antimetabolitos Antineoplásicos , Antineoplásicos , Desoxicitidina/análogos & derivados , Diuréticos/uso terapéutico , Quimioterapia Combinada , Femenino , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Persona de Mediana Edad , Compuestos Organoplatinos , Oxaliplatino , Neoplasias Pancreáticas/tratamiento farmacológico , Gemcitabina
8.
JOP ; 9(3): 251-66, 2008 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-18469437

RESUMEN

Each year, more than 30,000 Americans are diagnosed with pancreatic cancer. We have only made incremental advancements in treatment of pancreatic cancer despite our best efforts. Research has revealed that pancreatic cancer is a genetic disease which is associated with various forms of cancer associated genetic alterations. Identification and understanding of these carcinogenic gene alterations is the base upon which we can overcome drug resistance and develop novel treatment approaches. In this paper, we review current understanding of pharmacogenomics of pancreatic cancer treatment and address future direction of the field.


Asunto(s)
Resistencia a Antineoplásicos/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Farmacogenética , Anticuerpos Monoclonales/uso terapéutico , Citotoxinas/uso terapéutico , Sistemas de Liberación de Medicamentos , Predicción , Humanos , Individualidad , Mutación , Compuestos de Platino/uso terapéutico , Pirimidinas/uso terapéutico
9.
JOP ; 8(6): 799-805, 2007 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-17993734

RESUMEN

CONTEXT: Capecitabine has shown efficacy in treatment of metastatic pancreatic cancer. Several researchers have identified thymidine phosphorylase, dihydropyrimidine dehydrogenase, or their ratio as indicators of response to capecitabine in various cancers. CASE REPORT: We report two patients with metastatic pancreatic carcinoma who had long-term survivals on capecitabine after gemcitabine failure. These two cases prompted us to measure thymidine phosphorylase and dihydropyrimidine dehydrogenase levels to facilitate discourses regarding their relationship with efficacy of capecitabine. We also describe a novel method of measuring thymidine phosphorylase level from serum without an invasive tissue biopsy. One patient is alive as of today, with improved performance status, 50 months after capecitabine was started. CA 19-9 and CT scans remained stable during 57 cycles. Her thymidine phosphorylase level was 1.77 compared to a control level of 1.00. Dihydropyrimidine dehydrogenase level was 4.14 compared to a control level of 1.00. Their ratio was 0.43. The other patient was alive on capecitabine for 24 months. His performance status, bilirubin, AST, and ALT improved on capecitabine. CT scans and CA 19-9 remained stable during this period. He had thymidine phosphorylase level of 5.56, dihydropyrimidine dehydrogenase level of 2.74, and their ratio of 2.03. CONCLUSION: Capecitabine resulted in long term survivals in two patients with metastatic pancreatic cancer after gemcitabine failure. The use of capecitabine as second-line treatment in metastatic pancreatic cancer should be further explored along with the role of thymidine phosphorylase and dihydropyrimidine dehydrogenase levels in its activity. A non-invasive method of thymidine phosphorylase measurement we described should be validated in larger trials.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antimetabolitos Antineoplásicos/uso terapéutico , Desoxicitidina/análogos & derivados , Fluorouracilo/análogos & derivados , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/metabolismo , Biomarcadores/metabolismo , Capecitabina , Desoxicitidina/uso terapéutico , Dihidrouracilo Deshidrogenasa (NADP)/metabolismo , Femenino , Fluorouracilo/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/metabolismo , Farmacogenética , Análisis de Supervivencia , Timidina Fosforilasa/metabolismo , Resultado del Tratamiento , Gemcitabina
11.
Clin Cancer Res ; 22(6): 1318-24, 2016 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-26597302

RESUMEN

One of the key objectives of oncology first-in-human trials has often been to establish the maximum tolerated dose (MTD). However, targeted therapies might not exhibit dose-limiting toxicities (DLT) at doses significantly higher than sufficiently active doses, and there is frequently a limited ability to objectively quantify adverse events. Thus, while MTD-based determination of recommended phase II dose may have yielded appropriate dosing for some cytotoxics, targeted therapeutics (including monoclonal antibodies and/or immunotherapies) sometimes need alternative or complementary strategies to help identify dose ranges for a randomized dose-ranging study. One complementary strategy is to define a biologically efficacious dose (BED) using an "effect marker." An effect marker could be a target engagement, pharmacodynamic, or disease progression marker (change in tumor size for solid tumors or bone marrow blast count for some hematologic tumors). Although the concept of BED has been discussed extensively, we review specific examples in which the approach influenced oncology clinical development. Data extracted from the literature and the examples support improving dose selection strategies to benefit patients, providers, and the biopharmaceutical industry. Although the examples illustrate key contributions of effect markers in dose selection, no one-size-fits-all approach to dosing can be justified. Higher-than-optimal dosing can increase toxicity in later trials (and in clinical use), which can have a negative impact on efficacy (via lower adherence or direct sequelae of toxicities). Proper dose selection in oncology should follow a multifactorial decision process leading to a randomized, dose-ranging study instead of a single phase II dose.


Asunto(s)
Antineoplásicos/administración & dosificación , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Animales , Biomarcadores , Relación Dosis-Respuesta a Droga , Humanos , Dosis Máxima Tolerada , Neoplasias/metabolismo , Pronóstico , Resultado del Tratamiento
12.
J Clin Oncol ; 33(9): 1060-6, 2015 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-25605849

RESUMEN

PURPOSE: We determined the safety, pharmacokinetics, pharmacodynamics, and recommended phase II dose of MK-8776 (SCH 900776), a potent, selective checkpoint kinase 1 (Chk1) inhibitor, as monotherapy and in combination with gemcitabine in a first-in-human phase I clinical trial in patients with advanced solid tumor malignancies. PATIENTS AND METHODS: Forty-three patients were treated by intravenous infusion with MK-8776 at seven dose levels ranging from 10 to 150 mg/m(2) as monotherapy and then in combination with gemcitabine 800 mg/m(2) (part A, n = 26) or gemcitabine 1,000 mg/m(2) (part B, n = 17). Forty percent of patients had three or more prior treatment regimens, and one third of patients had previously received gemcitabine. RESULTS: As monotherapy, MK-8776 was well tolerated, with QTc prolongation (19%), nausea (16%), fatigue (14%), and constipation (14%) as the most frequent adverse effects. Combination therapy demonstrated a higher frequency of adverse effects, predominantly fatigue (63%), nausea (44%), decreased appetite (37%), thrombocytopenia (32%), and neutropenia (24%), as well as dose-related, transient QTc prolongation (17%). The median number of doses of MK-8776 administered was five doses, with relative dose-intensity of 0.96. Bioactivity was assessed by γ-H2AX ex vivo assay. Of 30 patients evaluable for response, two showed partial response, and 13 exhibited stable disease. CONCLUSION: MK-8776 was well tolerated as monotherapy and in combination with gemcitabine. Early evidence of clinical efficacy was observed. The recommended phase II dose is MK-8776 200 mg plus gemcitabine 1,000 mg/m(2) on days 1 and 8 of a 21-day cycle.


Asunto(s)
Desoxicitidina/análogos & derivados , Neoplasias/tratamiento farmacológico , Proteínas Quinasas/metabolismo , Pirazoles/administración & dosificación , Pirazoles/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Estudios de Cohortes , Citarabina/administración & dosificación , Desoxicitidina/administración & dosificación , Femenino , Histonas/metabolismo , Humanos , Infusiones Intravenosas , Células K562 , Masculino , Melanoma/tratamiento farmacológico , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Sarcoma/tratamiento farmacológico , Factores de Tiempo , Gemcitabina
15.
Clin Cancer Res ; 16(17): 4446-51, 2010 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-20736327

RESUMEN

PURPOSE: Several recent oral oncology drugs were labeled for administration in fasted states despite the fact that food increases their bioavailability. Because this was inconsistent with the principles of oral drug delivery, we hypothesized that there were inconsistencies across therapeutic areas. EXPERIMENTAL DESIGN: Oral agents approved by the U.S. Food and Drug Administration from January 2000 to May 2009 were included in our study. Comparison of the food labeling patterns between oncology and non-oncology drugs was made using Fisher's exact test. RESULTS: Of the 99 drugs evaluated, 34 showed significant food effects on bioavailability. When food markedly enhanced bioavailability, eight out of nine non-oncology drugs were labeled "fed" to take advantage of the food-drug interaction, whereas all oncology drugs (n = 3) were labeled to be administered in "fasted" states (Fisher's exact test, P = 0.01). CONCLUSIONS: Drug labeling patterns with respect to food-drug interactions observed with oncology drugs are in contradiction with fundamental pharmacologic principles, as exemplified in the labeling of non-oncology drugs. .


Asunto(s)
Antineoplásicos/administración & dosificación , Etiquetado de Medicamentos/normas , Interacciones Alimento-Droga , Preparaciones Farmacéuticas/administración & dosificación , Administración Oral , Antineoplásicos/farmacocinética , Área Bajo la Curva , Disponibilidad Biológica , Sistemas de Liberación de Medicamentos , Etiquetado de Medicamentos/estadística & datos numéricos , Ayuno , Alimentos , Humanos , Absorción Intestinal , Estados Unidos , United States Food and Drug Administration
16.
Curr Opin Obstet Gynecol ; 20(1): 40-6, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18197004

RESUMEN

PURPOSE OF REVIEW: We have made remarkable advances in treatment of breast cancer with combination chemotherapies, hormonal therapies, and modern targeted therapies. Triple negative breast cancers carry a poor prognosis, however, and they are insensitive to most available hormonal or targeted therapeutic agents thus far developed. A better understanding of pathophysiology, natural history, and currently available treatment options is necessary to improve outcomes of patients with triple negative breast cancer. RECENT FINDINGS: Gene expression profiling has allowed us to classify breast cancers into five subtypes based upon distinctive gene expression signatures. This subtyping is prognostic, and the recent literatures suggest that these 'molecular portraits' may be used to predict treatment outcomes in the future. SUMMARY: As we prepare for an era of targeted and individualized medicine, limited understanding of triple negative breast cancer biology presents a challenge in developing novel therapies. Identification of more molecular predictive signatures and their prospective validation will enable us to characterize triple negative breast cancers better and design optimal treatment modalities.


Asunto(s)
Antígenos de Neoplasias/metabolismo , Neoplasias de la Mama/metabolismo , Carcinoma Adenoide Quístico/metabolismo , Perfilación de la Expresión Génica , Negro o Afroamericano , Antígenos de Neoplasias/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/fisiopatología , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/fisiopatología , Supervivencia sin Enfermedad , Femenino , Humanos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA