RESUMO
The small molecule 3-bromopyruvate (3BP), is an anticancer molecule that acts by hindering glycolysis and mitochondrial function leading to energy depletion and consequently, to cell death. In this work we have focused on understanding how the glycolytic inhibition affects cancer cell structural features. We showed that 3BP leads to a drastic decrease in the levels of ß-actin and α-tubulin followed by disorganization and shrinkage of the cytoskeleton in breast cancer cells. 3BP inhibits cell migration and colony formation independently of the activity of metalloproteinases. To disclose if these structural alterations occurred prior to 3BP toxic effect, non-toxic concentrations of 3BP were used and we could observe that 3BP was able to inhibit energy production and induce loss of ß-actin and α-tubulin proteins. This was accompanied with alterations in cytoskeleton organization and an increase in E-cadherin levels which may indicate a decrease in cancer cells aggressiveness. In this study we demonstrate that 3BP glycolytic inhibition of breast cancer cells is accompanied by cytoskeleton disruption and consequently loss of migration ability, suggesting that 3BP can potentially be explored for metastatic breast cancer therapy.
Assuntos
Neoplasias da Mama , Tubulina (Proteína) , Actinas , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Citoesqueleto , Feminino , Humanos , PiruvatosRESUMO
OBJECTIVE: The objectives of this work were to fill the gap in the scientific literature and to evaluate the results of physical therapy treatments in individuals affected by chronic fatigue syndrome, considering only studies that employed a randomized controlled trial. METHODS: A systematic review was carried out according to PRISMA guidelines. Three bibliographic databases were searched: MEDLINE, Cochrane Library, and PEDro. The minimum prerequisites for papers to be included in the systematic review were that they had to (a) employ a randomized controlled trial; (b) be published in English; and (c) be published during the last ten years (2007-2017). The studies were evaluated according to Jadad score. RESULTS: Four studies were included. This systematic review suggests that a treatment that is more effective than all the others cannot be defined. This conclusion is related to the low number of investigated studies; therefore, the collected results cannot be generalized. CONCLUSION: Chronic fatigue syndrome is not yet a well-understood pathology, and the physical mechanisms that influence the outcomes still need more study. Rehabilitation programs that promote physiotherapy techniques such as exercise, mobilization, and body awareness (e.g., MRT and GET) are the most effective in reducing medium and long-term fatigue severity in CFS patients.
Assuntos
Terapia por Exercício/métodos , Síndrome de Fadiga Crônica/terapia , Modalidades de Fisioterapia , Exercício Físico , Humanos , Exame Físico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
AIM: Both Fluoropirimidine and Oxaliplatin (FluOx) are the most common anticancer drugs used to treat lung, colorectal, ovarian, breast, head/neck, and genitourinary cancers. However, the efficacy of FluOx-based therapy is often compromised because of the severe risk of toxicity. Stratification of patients for multidrug response is a promising strategy for cancer treatment and personalized therapy. METHODS: Here, we review the late findings on the most appropriate gene variants related to the toxicity in patients receiving FluOx chemotherapy. Several criteria were used to select a genotyping panel tests, including dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), Glutathione S-transferase (GSTP1), and ATP-binding cassette, subfamily C member 2 (ABCC2). RESULTS: Results of allelic status from 7 validated polymorphism assays, allow the stratification of the patients who are most likely to respond to FluOx treatments. Also, we will take in consideration the usefulness and costs of the methods used to detect these polymorphisms. CONCLUSIONS: With these pharmacogenomics markers, the oncologists will have new means based on the genetic profile of the individual, to make treatment decisions for their patients in order to maximize benefits and minimize toxicity.
Assuntos
Antineoplásicos/efeitos adversos , Fluoruracila/efeitos adversos , Compostos Organoplatínicos/efeitos adversos , Farmacogenética , Di-Hidrouracila Desidrogenase (NADP)/genética , Genótipo , Humanos , Proteína 2 Associada à Farmacorresistência Múltipla , Oxaliplatina , Polimorfismo Genético , Timidilato Sintase/genéticaRESUMO
Antiblastic treatment of hematological malignancies during pregnancy poses a number of issues related to the curability of the maternal disease, the need of a prompt treatment and the potential toxicity of chemotherapy for the fetus. Here we report the results of a systematic literature search about the management of the most frequent hematological malignancies that may occur during pregnancy, focusing on specific issues related to gestational age at diagnosis, fetal toxicity and efficacy on the maternal side. The standard approach in non-pregnant women is illustrated as reference.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Feminino , Doença de Hodgkin/tratamento farmacológico , Humanos , Leucemia/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , GravidezRESUMO
The incidence of acute myeloid leukemia (AML) increases with age, but results of intensive chemotherapy in elderly patients are disappointing. Non-pegylated liposomal formulations of doxorubicin (Myocet™) have been developed with the aim of reducing systemic and cardiac toxicity especially in the elderly. We evaluated the efficacy and toxicity profiles of fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) regimen given in association with Myocet™ in 35 patients with AML, median age 69 years (range 61-83 years). Nineteen (54.3%) had newly-diagnosed AML, twelve (34.3%) patients had secondary AML (ten with Myelodisplastic Syndrome, two with Primary Myelofibrosis) and 4 (11.4%) patients had had a late relapse (>12 months) of AML. Complete remission (CR) and partial remission (PR) were obtained in twenty-two (63%) and 3 (8.5%) patients, respectively. Seven (20%) patients showed a resistant disease. There were 3 early deaths (8.5%). Six patients (17%) experienced severe cardiovascular toxicity. The median overall survival (OS) was 12 months (range 1-52 months) with a median disease-free survival (DFS) of 20 months (range 1-48 months). One-year and two-year DFS were 78.9% and 26.7%, respectively. This study demonstrates that in elderly patients with AML, FLAG-Myocet combination shows promising efficacy response with acceptable toxicity, enabling most patients to receive further treatments, including transplantation procedures.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Citarabina/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Fator Estimulador de Colônias de Granulócitos , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Vidarabina/administração & dosagem , Vidarabina/análogos & derivadosRESUMO
The differential diagnosis and the identification of the source of ACTH in occult ectopic Cushing's syndrome due to a bronchial carcinoid still represents a challenge for the endocrinologist. We report our experience in six patients with occult bronchial carcinoid in whom extensive hormonal, imaging, and scintigraphic evaluation was performed. All patients presented with hypercortisolism associated with high plasma ACTH values. The CRH test and high dose dexamethasone suppression test suggested an ectopic source of ACTH in three of six patients. During bilateral inferior petrosal sinus sampling, none of the patients showed a central to peripheral ACTH gradient. At the time of diagnosis, none of the patients had radiological evidence of the ectopic source of ACTH, whereas pentetreotide scintigraphy identified the lesion in two of four patients. Finally, a chest computed tomography scan revealed the presence of a bronchial lesion in all patients, and pentetreotide scintigraphy identified four of six lesions. In all patients a bronchial carcinoid was found and removed. In one patient with scintigraphic evidence of residual disease after two operations, radioguided surgery, using a hand-held gamma probe after iv administration of radiolabeled pentetreotide, was performed; this allowed detection and removal of residual multiple mediastinal lymph node metastases. In conclusion, our data show that there is not a single endocrine test or imaging procedure accurate enough to diagnose and localize occult ectopic ACTH-secreting bronchial carcinoids. Radioguided surgery appears to be promising in the presence of multiple tumor foci and previous incomplete removal of the tumor.
Assuntos
Hormônio Adrenocorticotrópico/metabolismo , Neoplasias Brônquicas/metabolismo , Tumor Carcinoide/metabolismo , Somatostatina/análogos & derivados , Hormônio Adrenocorticotrópico/sangue , Adulto , Idoso , Neoplasias Brônquicas/diagnóstico , Neoplasias Brônquicas/terapia , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/terapia , Hormônio Liberador da Corticotropina/farmacologia , Feminino , Humanos , Radioisótopos de Índio , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Resultado do TratamentoAssuntos
Eritropoetina/administração & dosagem , Eritropoetina/economia , Ferro/administração & dosagem , Idoso , Custos e Análise de Custo , Esquema de Medicação , Feminino , Humanos , Ferro/economia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Recombinantes , Diálise Renal , Uremia/terapiaRESUMO
The multidrug resistance (MDR)-associated P-glycoprotein (P-gp) is a membrane transporter which carries, at the expense of MgATP hydrolysis, many amphiphilic molecules, such as the MDR-related cytotoxic drugs vincristine and vinblastine, and the MDR-reversing agents verapamil and progesterone. We have tested the effects on P-gp function of bromocriptine (BCT), an ergot alkaloid known as a D2 dopaminergic receptor agonist. BCT (at 4 microM) partially reverses the P-gp-mediated vincristine resistance of the Chinese hamster lung fibroblasts DC-3F/ADX, a MDR cell line. P-gp containing membrane vesicles prepared from the DC-3F/ADX cells exhibit, in the absence of any added drug, a basal MgATPase activity due to P-gp. BCT inhibits this basal ATPase activity, with a half-inhibiting concentration of 0.30 +/- 0.15 microM. BCT also inhibits the verapamil-induced P-gp ATPase stimulation competitively (Ki approximately 0.2 microM), and the progesterone-induced P-gp ATPase stimulation non-competitively (Ki approximately 0.07-0.10 microM). BCT also non-competitively inhibits the vinblastine-dependent P-gp ATPase activity within the same concentration range. Hydroxylated metabolites of BCT have different effects on P-gp ATPase, only the monohydroxylated being able to modulate both the basal and the drug-stimulated ATPase activities. In conclusion, these effects of BCT on P-gp function can be linked to a specific interaction with P-gp, probably involving inhibition of P-gp-mediated drug transport.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Bromocriptina/farmacologia , Animais , Transporte Biológico Ativo , Bromocriptina/metabolismo , Bromocriptina/farmacocinética , ATPase de Ca(2+) e Mg(2+)/antagonistas & inibidores , Linhagem Celular Transformada , Cricetinae , Agonistas de Dopamina/farmacologia , Resistência a Medicamentos , Resistência a Múltiplos Medicamentos , Hidroxilação , Cinética , Progesterona/farmacologia , Vincristina/farmacologiaRESUMO
We have developed two bromocriptine enzyme immunoassays with different specificities for applications in human and animal pharmacokinetic studies. The first assay uses antibodies directed against the cyclopeptide structure of bromocriptine, and is specific for untransformed bromocriptine. The second assay uses antibodies directed against the bromolysergic part of the molecule and allows the measurement of both bromocriptine and its metabolites. Enzymatic tracers were obtained by covalent coupling of bromocriptine analogs to acetylcholinesterase from the electric eel Electrophorus electricus. Both assays have a limit of detection of 10 pg/ml and a limit of quantification of 50 pg/ml. The specificity of the assays was determined following fractionation by high-performance liquid chromatography of rat samples obtained after administration of bromocriptine.
Assuntos
Bromocriptina/análise , Bromocriptina/metabolismo , Técnicas Imunoenzimáticas , Administração Oral , Animais , Especificidade de Anticorpos , Bromocriptina/administração & dosagem , Bromocriptina/imunologia , Reações Cruzadas , Técnicas Imunoenzimáticas/normas , Injeções Intravenosas , Masculino , Coelhos , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos TestesAssuntos
Neoplasias da Mama/diagnóstico , Linfoma/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Evolução Fatal , Feminino , Humanos , Linfoma/patologia , Linfoma/cirurgia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Fatores de TempoAssuntos
Cisto Pancreático/complicações , Pseudocisto Pancreático/complicações , Derrame Pleural/etiologia , Idoso , Drenagem , Humanos , Masculino , Pseudocisto Pancreático/diagnóstico por imagem , Derrame Pleural/diagnóstico por imagem , Derrame Pleural/terapia , Tomografia Computadorizada por Raios XRESUMO
Postoperative radiation after the removal of radiosensitive tumours may cause acute or chronic intestinal lesions. In some cases severe complications requiring one or more operations may arise even years later and unfortunately the morbidity and mortality rates are high. The paper presents a discussion of the clinical onset of these pictures as well as diagnostic and therapeutic possibilities in the light of personal experience and information obtained from the literature.
Assuntos
Intestinos/efeitos da radiação , Lesões por Radiação , Humanos , Mucosa Intestinal/efeitos da radiação , Lesões por Radiação/diagnóstico , Lesões por Radiação/etiologia , Lesões por Radiação/patologia , Lesões por Radiação/cirurgiaRESUMO
1,066 urine samples were assayed by beta-human chorionic gonadotrophin (beta-hCG) monoclonal pregnancy test with a sensitivity of 150 IU hCG/l. Tests were performed in 5 independent laboratories and results were compared with those of pregnancy tests which were used routinely. Urine samples which showed discordant results under evaluation were reassayed for beta-hCG using radioimmunoassay. 569 urine samples were from nonpregnant women, and a consistent result with comparison pregnancy tests was achieved in 97.19% of urine samples. The trial test from 389 urine samples of pregnant women was 99.49% in accordance with routine pregnancy tests. Results from 108 urine samples of women over 40 years of age indicate the high specificity of the new beta-hCG monoclonal pregnancy test. Titration experiments showed 63% positive tests at 150 IU beta-hCG/l. Data presented combine to suggest that this new monoclonal pregnancy test is a valuable aid in diagnosing early pregnancy. It may also be used in the diagnosis of tubal pregnancy and in other ectopic processes.
Assuntos
Anticorpos Monoclonais/urina , Gonadotropina Coriônica/urina , Fragmentos de Peptídeos/urina , Testes Imunológicos de Gravidez/métodos , Adulto , Gonadotropina Coriônica Humana Subunidade beta , Feminino , Testes de Inibição da Hemaglutinação , Humanos , GravidezRESUMO
Melanophores of Papiliochromis ramirezi aggregate their melanosomes in the presence of catecholamines. Their order of potency are: at 10(-4) M, norepinephrine greater than isoproterenol = epinephrine; at 10(-6) and 10(-8) M, norepinephrine = isoproterenol greater than epinephrine. These effects are antagonized not only by phentolamine but also by propranolol. The catecholamines are unable to induce pigment dispersion. Melanosome dispersion is obtained with cholinergic drugs and the order of potency is nicotine greater than acetylcholine = pilocarpine. Their effects are inhibited by atropine and also by d-tubocurarine and potentiated by physostigmine. The evidences suggest the presence of undifferentiated adrenoceptors, related to the melanosome aggregation and undifferentiated cholinoceptors related to the melanosome dispersion.