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1.
Support Care Cancer ; 27(8): 2789-2797, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30535882

RESUMO

PURPOSE: Acute leukemia (AL) is associated with substantial morbidity and mortality. We assessed the prevalence and correlates of pain in patients with newly diagnosed or relapsed AL. METHODS: Patients with newly diagnosed or relapsed AL admitted to a comprehensive cancer center completed the Memorial Symptom Assessment Scale (MSAS), which assesses prevalence, severity, and distress associated with pain and other symptoms. Factors associated with severe pain were assessed using logistic regression. Two raters completed chart reviews in duplicate for patients with severe pain (MSAS severity ≥ 3/4) to determine the site of pain. RESULTS: Three hundred eighteen patients were recruited from January 2008 to October 2013: 245 (77.0%) had acute myeloid or acute promyelocytic leukemia (AML/APL) and 73 (23.0%) had acute lymphoblastic leukemia (ALL); 289 (90.9%) were newly diagnosed and 29 (9.1%) had relapsed disease. Pain was reported in 156/318 (49.2%), of whom 55/156 (35.3%) reported severe pain (≥ 3/4). Pain was associated with all psychological symptoms (all p < 0.005) and some physical symptoms. Severe pain was associated with younger age (p = 0.02), worse performance status (p = 0.04), ALL diagnosis (p = 0.04), and time from onset of chemotherapy (p = 0.03), with pain peaking at 4 weeks after chemotherapy initiation. The most common sites of severe pain were oropharynx (22; 40%), head (12; 21.8%), and abdomen (11; 20%). Only 3 patients (0.9%) were referred to the symptom control/palliative care team during the month prior to or following assessment. CONCLUSIONS: Pain is frequent, distressing, and predictable in patients undergoing induction chemotherapy for AL. Further research is needed to assess the efficacy of early supportive care in this population.


Assuntos
Dor do Câncer/diagnóstico , Dor do Câncer/epidemiologia , Leucemia/complicações , Leucemia/epidemiologia , Dor/diagnóstico , Doença Aguda , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Dor do Câncer/etiologia , Feminino , Humanos , Leucemia/diagnóstico , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Dor/epidemiologia , Dor/etiologia , Medição da Dor , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prevalência , Recidiva , Adulto Jovem
2.
Cancer Res ; 75(12): 2478-88, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-26077472

RESUMO

Treatment regimens for acute myeloid leukemia (AML) continue to offer weak clinical outcomes. Through a high-throughput cell-based screen, we identified avocatin B, a lipid derived from avocado fruit, as a novel compound with cytotoxic activity in AML. Avocatin B reduced human primary AML cell viability without effect on normal peripheral blood stem cells. Functional stem cell assays demonstrated selectivity toward AML progenitor and stem cells without effects on normal hematopoietic stem cells. Mechanistic investigations indicated that cytotoxicity relied on mitochondrial localization, as cells lacking functional mitochondria or CPT1, the enzyme that facilitates mitochondria lipid transport, were insensitive to avocatin B. Furthermore, avocatin B inhibited fatty acid oxidation and decreased NADPH levels, resulting in ROS-dependent leukemia cell death characterized by the release of mitochondrial proteins, apoptosis-inducing factor, and cytochrome c. This study reveals a novel strategy for selective leukemia cell eradication based on a specific difference in mitochondrial function.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Extratos Vegetais/farmacologia , Óleos de Plantas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Cromatografia Líquida/métodos , Frutas/química , Ensaios de Triagem em Larga Escala/métodos , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Espectrometria de Massas/métodos , Camundongos , Mitocôndrias/metabolismo , Oxirredução , Persea/química , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Science ; 344(6180): 208-11, 2014 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-24723613

RESUMO

Genome-wide characterization of the in vivo cellular response to perturbation is fundamental to understanding how cells survive stress. Identifying the proteins and pathways perturbed by small molecules affects biology and medicine by revealing the mechanisms of drug action. We used a yeast chemogenomics platform that quantifies the requirement for each gene for resistance to a compound in vivo to profile 3250 small molecules in a systematic and unbiased manner. We identified 317 compounds that specifically perturb the function of 121 genes and characterized the mechanism of specific compounds. Global analysis revealed that the cellular response to small molecules is limited and described by a network of 45 major chemogenomic signatures. Our results provide a resource for the discovery of functional interactions among genes, chemicals, and biological processes.


Assuntos
Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Resistência a Medicamentos/genética , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla/métodos , Bibliotecas de Moléculas Pequenas/farmacologia , Linhagem Celular Tumoral , Haploinsuficiência , Humanos , Farmacogenética , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética
4.
Blood ; 117(6): 1986-97, 2011 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-21135258

RESUMO

D-cyclins are universally dysregulated in multiple myeloma and frequently overexpressed in leukemia. To better understand the role and impact of dysregulated D-cyclins in hematologic malignancies, we conducted a high-throughput screen for inhibitors of cyclin D2 transactivation and identified 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161), which inhibited the expression of cyclins D1, D2, and D3 and arrested cells at the G(0)/G(1) phase. After D-cyclin suppression, S14161 induced apoptosis in myeloma and leukemia cell lines and primary patient samples preferentially over normal hematopoietic cells. In mouse models of leukemia, S14161 inhibited tumor growth without evidence of weight loss or gross organ toxicity. Mechanistically, S14161 inhibited the activity of phosphoinositide 3-kinase in intact cells and the activity of the phosphoinositide 3-kinases α, ß, δ, and γ in a cell-free enzymatic assay. In contrast, it did not inhibit the enzymatic activities of other related kinases, including the mammalian target of rapamycin, the DNA-dependent protein kinase catalytic subunit, and phosphoinositide-dependent kinase-1. Thus, we identified a novel chemical compound that inhibits D-cyclin transactivation via the phosphoinositide 3-kinase/protein kinase B signaling pathway. Given its potent antileukemia and antimyeloma activity and minimal toxicity, S14161 could be developed as a novel agent for blood cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Benzopiranos/farmacologia , Ciclina D/antagonistas & inibidores , Ciclina D/genética , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Ativação Transcricional/efeitos dos fármacos , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Sequência de Bases , Benzopiranos/química , Transporte Biológico Ativo/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Primers do DNA/genética , Avaliação Pré-Clínica de Medicamentos , Fase G1/efeitos dos fármacos , Humanos , Células K562 , Leucemia/genética , Leucemia/patologia , Camundongos , Camundongos SCID , Estrutura Molecular , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Células NIH 3T3 , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Apoptosis ; 13(3): 413-22, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18181020

RESUMO

p53 regulates apoptosis and the cell cycle through actions in the nucleus and cytoplasm. Altering the subcellular localization of p53 can alter its biological function. Therefore, small molecules that change the localization of p53 would be useful chemical probes to understand the influence of subcellular localization on the function of p53. To identify such molecules, a high-content screen for compounds that increased the localization of p53 to the nucleus or cytoplasm was developed, automated, and conducted. With this image-based assay, we identified ellipticine that increased the nuclear localization of GFP-mutant p53 protein but not GFP alone in Saos-2 osteosarcoma cells. In addition, ellipticine increased the nuclear localization of endogenous p53 in HCT116 colon cancer cells with a resultant increase in the transactivation of the p21 promoter. Increased nuclear p53 after ellipticine treatment was not associated with an increase in DNA double stranded breaks, indicating that ellipticine shifts p53 to the nucleus through a mechanism independent of DNA damage. Thus, a chemical biology approach has identified a molecule that shifts the localization of p53 and enhances its nuclear activity.


Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Elipticinas/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo , Inibidor de Quinase Dependente de Ciclina p21/fisiologia , Dano ao DNA , Avaliação Pré-Clínica de Medicamentos , Proteínas de Fluorescência Verde/metabolismo , Humanos , Leupeptinas/farmacologia , Osteossarcoma , Proteínas Recombinantes de Fusão/metabolismo , Tapsigargina/farmacologia , Proteína Supressora de Tumor p53/genética
7.
Blood ; 110(12): 4047-54, 2007 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-17875808

RESUMO

The oncogene c-maf is frequently overexpressed in multiple myeloma cell lines and patient samples and contributes to increased cellular proliferation in part by inducing cyclin D2 expression. To identify regulators of c-maf, we developed a chemical screen in NIH3T3 cells stably overexpressing c-maf and the cyclin D2 promoter driving luciferase. From a screen of 2400 off-patent drugs and chemicals, we identified glucocorticoids as c-maf-dependent inhibitors of cyclin D2 transactivation. In multiple myeloma cell lines, glucocorticoids reduced levels of c-maf protein without influencing corresponding mRNA levels. Subsequent studies demonstrated that glucocorticoids increased ubiquitination-dependent degradation of c-maf and up-regulated ubiquitin C mRNA. Moreover, ectopic expression of ubiquitin C recapitulated the effects of glucocorticoids, demonstrating regulation of c-maf protein through the abundance of the ubiquitin substrate. Thus, using a chemical biology approach, we identified a novel mechanism of action of glucocorticoids and a novel mechanism by which levels of c-maf protein are regulated by the abundance of the ubiquitin substrate.


Assuntos
Glucocorticoides/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Proto-Oncogênicas c-maf/metabolismo , Ubiquitina/metabolismo , Ubiquitinação/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Animais , Ciclina D2 , Ciclinas/genética , Ciclinas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Glucocorticoides/química , Luciferases/genética , Luciferases/metabolismo , Camundongos , Células NIH 3T3 , Regiões Promotoras Genéticas/genética , Ativação Transcricional/efeitos dos fármacos
8.
Endocrinology ; 147(5): 2357-67, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16484322

RESUMO

ACTH regulates the steroidogenic capacity, size, and structural integrity of the adrenal cortex through a series of actions involving changes in gene expression; however, only a limited number of ACTH-regulated genes have been identified, and these only partly account for the global effects of ACTH on the adrenal cortex. In this study, a National Institute on Aging 15K mouse cDNA microarray was used to identify genome-wide changes in gene expression after treatment of Y1 mouse adrenocortical cells with ACTH. ACTH affected the levels of 1275 annotated transcripts, of which 46% were up-regulated. The up-regulated transcripts were enriched for functions associated with steroid biosynthesis and metabolism; the down- regulated transcripts were enriched for functions associated with cell proliferation, nuclear transport and RNA processing, including alternative splicing. A total of 133 different transcripts, i.e. only 10% of the ACTH-affected transcripts, were represented in the categories above; most of these had not been described as ACTH-regulated previously. The contributions of protein kinase A and protein kinase C to these genome-wide effects of ACTH were evaluated in microarray experiments after treatment of Y1 cells and derivative protein kinase A-defective mutants with pharmacological probes of each pathway. Protein kinase A-dependent signaling accounted for 56% of the ACTH effect; protein kinase C-dependent signaling accounted for an additional 6%. These results indicate that ACTH affects the expression profile of Y1 adrenal cells principally through cAMP- and protein kinase A- dependent signaling. The large number of transcripts affected by ACTH anticipates a broader range of actions than previously appreciated.


Assuntos
Córtex Suprarrenal/citologia , Hormônio Adrenocorticotrópico/metabolismo , Regulação da Expressão Gênica , Processamento Alternativo , Animais , Linhagem Celular , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Primers do DNA/química , DNA Complementar/metabolismo , Regulação para Baixo , Expressão Gênica , Genoma , Camundongos , Modelos Biológicos , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Proteína Quinase C/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Esteroides/metabolismo , Regulação para Cima
9.
Support Care Cancer ; 10(3): 247-52, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11904790

RESUMO

The number of long-term survivors of autologous blood and marrow transplantation (ABMT) is increasing, but little is known about the models of care used to follow these patients. Such information would help in comparison of different methods of follow-up and allow other centers to create programs to follow their survivors. Here we describe a multidisciplinary long-term follow-up clinic for survivors of ABMT and report patient satisfaction with the clinic and economic analysis 1.5 years after its inception. In its first 1.5 years of operation, 83 new patients were seen in the clinic. Patients were evaluated a median of 4.0 years after ABMT (range 4.9 months to 12 years) and were a median of 48.5 years (range 22.5-69.0 years) old. Patients received their ABMT for non-Hodgkin's lymphoma ( n=26), Hodgkin's disease ( n=18), acute myeloid leukemia ( n=18), multiple myeloma ( n=15), breast cancer ( n=5), or desmoplastic round-cell tumor ( n=1). Patient satisfaction was assessed 1.5 years after the establishment of the long-term follow-up clinic by means of a self-report questionnaire. Seventy-five percent of patients returned the survey. Waiting times in the clinic were short, with 70% of patients seen within 30 minutes of arrival. Overall, patients were very satisfied with the new clinic model, with 85% patients reporting that the clinic met their expectations. An economic analysis indicated that the estimated annual cost of operating the clinic was approximately $53,000, which translates into $440 per patient visit, $962 per new patient or $172 per patient visit with the clinic operating at peak capacity. In conclusion, we present an inexpensive model of care for ABMT survivors that can be extended to adult survivors of malignancy not treated by ABMT.


Assuntos
Transfusão de Sangue Autóloga , Transplante de Medula Óssea , Adulto , Idoso , Neoplasias da Mama/terapia , Seguimentos , Doença de Hodgkin/terapia , Humanos , Leucemia Mieloide/terapia , Linfoma não Hodgkin/terapia , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Satisfação do Paciente , Sobreviventes , Transplante Autólogo
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