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1.
CA Cancer J Clin ; 67(5): 411-431, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28683174

RESUMO

Answer questions and earn CME/CNE Chronic hepatitis C virus (HCV) infection affects millions of people worldwide and is associated with cancer. Direct-acting antivirals (DAAs) have changed HCV treatment paradigms, but little is known about the management of HCV infection in patients with cancer. The substantial burden of HCV infection and the inconclusive evidence regarding its detection and management in patients with cancer prompted the authors to review the literature and formulate recommendations. Patients for whom HCV screening is recommended included all patients with hematologic malignancies, hematopoietic cell transplantation candidates, and patients with liver cancer. There is a lack of consensus-based recommendations for the identification of HCV-infected patients with other types of cancer, but physicians may at least consider screening patients who belong to groups at heightened risk of HCV infection, including those born during 1945 through 1965 and those at high risk for infection. Patients with evidence of HCV infection should be assessed by an expert to evaluate liver disease severity, comorbidities associated with HCV infection, and treatment opportunities. DAA therapy should be tailored on the basis of patient prognosis, type of cancer, cancer treatment plan, and hepatic and virologic parameters. HCV-infected patients with cancer who have cirrhosis (or even advanced fibrosis) and those at risk for liver disease progression, especially patients with HCV-associated comorbidities, should have ongoing follow-up, regardless of whether there is a sustained virologic response, to ensure timely detection and treatment of hepatocellular carcinoma. HCV infection and its treatment should not be considered contraindications to cancer treatment and should not delay the initiation of an urgent cancer therapy. CA Cancer J Clin 2017. © 2017 American Cancer Society. CA Cancer J Clin 2017;67:411-431. © 2017 American Cancer Society.


Assuntos
Hepatite C Crônica , Neoplasias Hepáticas/virologia , Antivirais/uso terapêutico , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/terapia
2.
Cancer J ; 22(3): 190-5, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27341597

RESUMO

Initial investigations of immune-checkpoint therapy targeting Programmed cell death protein 1/programed death ligand 1 in unselected colorectal cancer (CRC) has shown limited to no activity. However, a subset of CRC, characterized by mismatch deficiency or microsatellite instability high (MSI-high), has shown robust early signals of antitumor activity with PD1 targeting. It is now clear that MSI-high CRC represents a unique molecular and immunological tumor subset. Further study and understanding of the immunological microenvironment of these tumors will be critical to continued success with immune-based approaches in MSI-high CRC. This review discusses the current biological understanding of MSI-high CRC and outlines the current and ongoing clinical trials investigating immunotherapy.


Assuntos
Neoplasias Colorretais/etiologia , Neoplasias Colorretais/terapia , Reparo de Erro de Pareamento de DNA , Imunoterapia , Antígenos de Neoplasias/imunologia , Neoplasias Colorretais/patologia , Predisposição Genética para Doença , Humanos , Imunoterapia/métodos , Instabilidade de Microssatélites , Mutação , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
3.
J Pharmacol Exp Ther ; 314(1): 191-200, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15784656

RESUMO

Glucocorticoids amplify endogenous glucose production in type 2 diabetes by increasing hepatic glucose output. Systemic glucocorticoid blockade lowers glucose levels in type 2 diabetes, but with several adverse consequences. It has been proposed, but never demonstrated, that a liver-selective glucocorticoid receptor antagonist (LSGRA) would be sufficient to reduce hepatic glucose output (HGO) and restore glucose control to type 2 diabetic patients with minimal systemic side effects. A-348441 [(3b,5b,7a,12a)-7,12-dihydroxy-3-{2-[{4-[(11b,17b)-17-hydroxy-3-oxo-17-prop-1-ynylestra-4,9-dien-11-yl] phenyl}(methyl)amino]ethoxy}cholan-24-oic acid] represents the first LSGRA with significant antidiabetic activity. A-348441 antagonizes glucocorticoid-up-regulated hepatic genes, normalizes postprandial glucose in diabetic mice, and demonstrates synergistic effects on blood glucose in these animals when coadministered with an insulin sensitizer. In insulin-resistant Zucker fa/fa rats and fasted conscious normal dogs, A-348441 reduces HGO with no acute effect on peripheral glucose uptake. A-348441 has no effect on the hypothalamic pituitary adrenal axis or on other measured glucocorticoid-induced extrahepatic responses. Overall, A-348441 demonstrates that an LSGRA is sufficient to reduce elevated HGO and normalize blood glucose and may provide a new therapeutic approach for the treatment of type 2 diabetes.


Assuntos
Glicemia/metabolismo , Ácidos Cólicos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Estrona/análogos & derivados , Glucose/metabolismo , Fígado/metabolismo , Receptores de Glucocorticoides/antagonistas & inibidores , Células 3T3 , Adipócitos/metabolismo , Animais , Biotransformação/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Ácidos Cólicos/metabolismo , Diabetes Mellitus Tipo 2/sangue , Cães , Sinergismo Farmacológico , Estrona/metabolismo , Estrona/farmacologia , Glucocorticoides/farmacologia , Glutamato-Amônia Ligase/metabolismo , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Obesidade/metabolismo , Prednisolona/farmacologia , Ratos , Ratos Zucker , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rosiglitazona , Tiazolidinedionas/farmacologia , Tirosina Transaminase/metabolismo
4.
J Med Chem ; 47(17): 4213-30, 2004 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-15293993

RESUMO

Hepatic blockade of glucocorticoid receptors (GR) suppresses glucose production and thus decreases circulating glucose levels, but systemic glucocorticoid antagonism can produce adrenal insufficiency and other undesirable side effects. These hepatic and systemic responses might be dissected, leading to liver-selective pharmacology, when a GR antagonist is linked to a bile acid in an appropriate manner. Bile acid conjugation can be accomplished with a minimal loss of binding affinity for GR. The resultant conjugates remain potent in cell-based functional assays. A novel in vivo assay has been developed to simultaneously evaluate both hepatic and systemic GR blockade; this assay has been used to optimize the nature and site of the linker functionality, as well as the choice of the GR antagonist and the bile acid. This optimization led to the identification of A-348441, which reduces glucose levels and improves lipid profiles in an animal model of diabetes.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/síntese química , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/síntese química , Fígado/metabolismo , Receptores de Glucocorticoides/antagonistas & inibidores , Animais , Ácidos e Sais Biliares/química , Sítios de Ligação , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Células CHO , Células Cultivadas , Simulação por Computador , Cricetinae , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Glucose/biossíntese , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiologia , Masculino , Camundongos , Modelos Moleculares , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 14(9): 2047-50, 2004 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-15080976

RESUMO

Biaryl amides derived from a reported series of ureas 1 were evaluated and found to be potent human glucagon receptor antagonists. The benzofuran analogue 6i was administered in Sprague-Dawley rats and blocked the effects of an exogenous glucagon challenge.


Assuntos
Amidas/farmacologia , Receptores de Glucagon/antagonistas & inibidores , Amidas/química , Animais , Haplorrinos , Humanos , Camundongos , Ratos , Ratos Sprague-Dawley
6.
Curr Opin Investig Drugs ; 4(4): 421-9, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12808881

RESUMO

The discovery of antidiabetic agents that inhibit hepatic glucose production is a popular and potentially fruitful research area for the pharmaceutical research community. Metformin, a marketed agent with this mechanism of action, is widely used for the treatment of type 2 diabetes, however, more efficacious agents are sought. A number of promising proteins are being targeted for modulation by new compounds, including the glucagon receptor, glycogen phosphorylase, glucocorticoid receptor, 11 beta-hydroxysteroid dehydrogenase-1, fructose-1,6-bisphosphatase, carnitine palmitoyltransferase-1, glycogen synthase kinase-3, glucose-6-phosphate T1 translocase and the A2B receptor. Compounds designed to work against these targets are at the early clinical or preclinical phase of study. Glucagon receptor antagonists, glycogen phosphorylase inhibitors, 11 beta-hydroxysteroid dehydrogenase-1 inhibitors, carnitine palmitoyltransferase-1 inhibitors and fructose-1,6-bisphosphatase inhibitors are, or have been, clinically evaluated. Preclinical studies against the other targets have yielded compounds that demonstrate efficacy in diabetic animal models and clinical activity will continue.


Assuntos
Glucose/biossíntese , Fígado/metabolismo , 11-beta-Hidroxiesteroide Desidrogenases , Animais , Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Frutose-Bifosfatase/antagonistas & inibidores , Gluconeogênese/efeitos dos fármacos , Glicogênio Fosforilase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Fígado/efeitos dos fármacos , Glicogênio Hepático/biossíntese , Metformina/farmacologia , Antagonistas de Receptores Purinérgicos P1 , Receptores de Glucagon/antagonistas & inibidores , Receptores de Glucocorticoides/antagonistas & inibidores
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