El ácido valproico como agente sensibilizador al tratamiento anticáncer / Valproic acid as a sensitizing agent in anticancer treatment

Resumen El ácido valproico es un fármaco antiepiléptico con más de 50 años de uso clínico. En la década pasada se descubrieron sus efectos anticancerígenos. El análisis de grupos de pacientes que utilizaron este fármaco durante años ha mostrado que disminuye la frecuencia de cáncer de cabeza y cuello. Estudios recientes evidencian el efecto anticáncer al combinar el ácido valproico con la quimioterapia, terapia biológica e inhibidores de sistemas antioxidantes, con resultados excepcionales. En esta revisión se analiza el metabolismo del ácido valproico y su aplicación contra el cáncer.

Abstract Valproic acid is an antiepileptic drug with more than 50 years of clinical use. In the past decade, its anticancer effects were discovered. Analyses in groups of patients who used this drug for years have shown that it decreases the frequency of head and neck cancer. Recent studies show the anticancer effect of combining valproic acid with chemotherapy, biological therapy and antioxidant systems inhibitors, with exceptional results. In this review, we analyze the metabolism of valproic acid and its application against cancer.

Efeito da revascularização renal sobre a evolução da disfunção renal na nefropatia isquêmica aterosclerótica / Effect of renal revascularization on the development of renal dysfunction in atherosclerotic ischemic nephropathy

A doença renal crônica (DRC) é caracterizada por uma perda progressiva da função renal e suas principais causas são hipertensão arterial (HA) e diabete melito. Entre as causas de HA, podemos destacar a doença renal aterosclerótica (DRA). O desenvolvimento de DRC nos pacientes com DRA parece ser decorrente não apenas do acometimento das artérias renais principais, mas também da microcirculação renal, o que pode justificar o fato de o sucesso do procedimento não garantir uma melhora da evolução da DRC. Até o presente momento, não existe evidência de benefício da angioplastia em relação ao tratamento clínico exclusivo nos pacientes com DRA. O presente trabalho analisa os estudos mais significantes sobre os desfechos renais em pacientes portadores de DRA submetidos à revascularização ou ao tratamento clínico exclusivo.

Chronic kidney disease (CKD) is characterized by a progressive loss of renal function and its main causes are hypertension and diabetes mellitus. Among the causes of hypertension is atherosclerotic renal disease (ARD). The development of CKD in patients with ARD appears to be due not only to the involvement of the main renal arteries, but also of the renal microcirculation, which may explain the fact that the success of the procedure does not guarantee an improvement in the progression of CKD. To date there is no evidence of benefit of angioplasty compared to medical treatment alone in patients with ARD. The present paper analyzes the most significant studies on renal outcomes in patients with ARD undergoing revascularization or medical treatment alone.

Boys in white: um clássico da pesquisa qualitativa completa cinquenta anos / Boys in white: a classic of qualitative research turns 50

O artigo analisa o livro Boys in white: student culture in medical school, de Howard S. Becker, Blanche Geer, Everett C. Hughes e Anselm Strauss, considerado um dos modelos de pesquisa qualitativa em sociologia. A análise aborda as trajetórias dos autores, do livro, da pesquisa qualitativa e dos estudantes de medicina, enfatizando sua importância nas origens da sociologia médica e da sociologia da educação médica. Na trajetória dos autores são apresentados aspectos biobibliográficos; na da pesquisa qualitativa, o modo como essa metodologia de investigação atravessa a construção do trabalho de campo; e na dos estudantes, sua forma de atravessar os primeiros anos da escola médica e construir sua própria “cultura do estudante”.

This article analyzes Boys in white: student culture in medical schoolby Howard S. Becker, Blanche Geer, Everett C. Hughes and Anselm Strauss, considered a model of qualitative research in sociology. The analysis investigates the trajectories of the authors, the book, qualitative analysis, and the medical students, emphasizing their importance in the origins of medical sociology and the sociology of medical education. In the trajectory of the authors, bibliographical information is given. The trajectory of qualitative research focuses on how this methodology influences the construction of the field. The investigation of the students’ trajectory shows how they progress through their first years at medical school to build their own student culture.

Clinical and economic aspects of the use of rituximab in non-Hodgkin's lymphoma

Non-Hodgkin's lymphoma (NHL) consists of a group of neoplasias involving mainly B cells and represents 90% of all lymphomas. The current available therapy is based on chemotherapy associated with the monoclonal antibody rituximab (Mab Thera(r)), which targets the CD20 protein, present in over 80% of NHL mature B cells. Recent clinical reports show a preference for combining the benefits of immunotherapy and adjuvant chemotherapy, thus generating safe and effective alternative treatments. The current review aimed at evaluating various aspects related to the use of rituximab for NHL, highlighting the possible inhibitory mechanisms of cell proliferation, the achieved clinical results, and the expected clinical and economic outcomes of treatments. The results from clinical tests indicate the need for a better understanding of the critical mechanisms of action of this antibody, which may maximize its therapeutic efficacy. This therapy not only represents a viable option to treat most types of NHLs, especially when associated with conventional chemotherapy, but also offers cost-utility and cost-effectiveness advantages.

O Linfoma não-Hodgkin (LNH) consiste em um grupo de neoplasias envolvendo, principalmente, as células B e representa 90% de todos os linfomas. A terapia atual disponível é baseada em quimioterapia associada ao anticorpo monoclonal rituximabe (Mab Thera(r)), que tem como alvo a proteína CD20, presente em mais de 80% das células B maduras do LNH. Recentes relatórios clínicos mostram preferência para combinar os benefícios da quimioterapia adjuvante e imunoterapia, gerando alternativas de tratamentos seguro e eficaz. O trabalho de revisão teve por objetivo avaliar vários aspectos relacionados à aplicação do rituximabe no LNH, destacando os possíveis mecanismos inibitórios da proliferação celular, os resultados clínicos obtidos e as implicações clínicas e econômicas esperadas para o tratamento. Os resultados de testes clínicos indicam a necessidade de uma melhor compreensão dos mecanismos críticos de ação deste anticorpo, que poderão maximizar a sua eficácia terapêutica. Essa terapia não representa apenas uma opção viável para o tratamento da maioria dos tipos de LNH, principalmente quando associado à quimioterapia convencional, mas, também, oferece vantagens em termos de custo-utilidade e custo-efetividade.

Expression of Heat Shock Protein 70 Modulates the Chemoresponsiveness of Pancreatic Cancer

BACKGROUND/AIMS: Heat shock protein (HSP) 70 is constitutively overexpressed in pancreatic cancer cells (PCCs) and appears to confer protection against chemotherapeutics. We investigated whether modulating HSP 70 increases chemoresponsiveness to gemcitabine in PCCs. METHODS: Varying concentrations of quercetin and gemcitabine, either alone or in combination, were added to PCCs (Panc-1 and MiaPaCa-2). MTT assay was performed to analyze cell viability. HSP 70 expression was assessed by Western blot analysis. Apoptosis was determined by measuring caspase-3 activity. Western blot for the LC3-II protein detected the presence of autophagy. RESULTS: HSP 70 levels were not affected by the incubation of Panc-1 and MiaPaCa-2 cells with gemcitabine, whereas with quercetin, the levels were reduced in both cell lines. The viability of both Panc-1 and MiaPaCa-2 cells significantly decreased with gemcitabine treatment but not with quercetin. A combination of gemcitabine and quercetin decreased the viability of both cell lines in a dose-dependent manner, which was more pronounced than gemcitabine treatment alone. Treatment with either gemcitabine or quercetin augmented caspase-3 activity in both cell lines, and a combination of these compounds further potentiated caspase-3 activity. LC3-II protein expression was negligible with gemcitabine treatment but marked with quercetin. The addition of gemcitabine to quercetin did not potentiate LC3-II protein expression. CONCLUSIONS: Modulation of HSP 70 expression with quercetin enhanced the chemoresponsiveness of PCCs to gemcitabine. The mechanism of cell death was both apoptosis and autophagy.

Novel EGFR-TK Inhibitor EKB-569 Inhibits Hepatocellular Carcinoma Cell Proliferation by AKT and MAPK Pathways

Epidermal growth factor receptor (EGFR)-targeted therapies have been effective in some cancers, but not in hepatocellular carcinoma (HCC). The aim of this study was to investigate the drug potential to overcome multi-drug resistance in HCC cells. Thirteen drug-sensitive HCC cells were assessed using the CCK-8 assay. G0-G1 arrest was measured by FACS. Western blot analysis was used to detect the key enzymes in both the Ras/Raf and PI3K pathways. When establishing the IC50 of HCC to several drugs, including EKB-569, sorafenib, erlotinib, gefitinib, pazopanib, and brivanib, SK-Hep1 cells treated with EKB-569 have shown the highest (72.8%-86.4%) G0-G1 arrest and decreased the phosphorylation of AKT and ERK at the protein level. We found that EKB-569 had higher efficacy in HCC, compared to first generation, reversible EGFR-TK inhibitors. Furthermore, the combination of sorafenib and EKB-569 showed a synergistic effect to inhibit proliferation of SNU-475, previously the most resistant cell to EGFR-TKIs. Therefore, novel EKB-569 in combination with sorafenib may be able to overcome HCC resistance to EGFR-TK inhibitors.

Recaída sistémica con compromiso de SNC de linfoma Hodgkin y respuesta al esquema Gemcitabina/Vinorelbina / Systemic Relapse with involvement of the CNS by Hodgkin's Lymphoma: response to gemcitabine/Vinorelbine Scheme

El compromiso del sistema nervioso central (SNC) por Linfoma de Hodgkin es infrecuente. El tratamiento con Gemcitabina/Vinorelbina es efectivo y bien tolerado en pacientes con Linforma de Hodkgin recaídos/refractarios.

Central nervous system involvement by Hodgkin is rare. Gemcitabine/Vinorelbine is an effective and well tolerated regimen for patients with relapsed and refractory Hodgkin's lymphoma.

Antibodies against 9-O-acetylated sialic acids in childhood acute lymphoblastic leukemia: a two-year study with 186 samples following protocol MCP 943.

Initial studies have revealed an enhanced surface expression of 9-O-acetylated sialoglycoconjugates (9-OAcSGs) on lymphoblasts concomitant with high titers of antibodies (anti-9-OAcSGs) in childhood acute lymphoblastic leukemia (ALL). This study was undertaken in 186 coded samples from 69 ALL patients to evaluate if antibodies against these sialoglycans could monitor response to the treatment. An ELISA was developed using bovine submaxillary mucin (BSM) containing high % of 9-O-acetylated sialic acids (9-OAcSA) as the capture antigen, to investigate serum levels of anti 9-OAcSGs in a single-center series of pediatric, clinically-diagnosed and immunophenotypically confirmed ALL patients, as compared to 130 healthy controls. At presentation, a 3.8-fold increase in anti-9-OAcSGs levels was detected in 63/69 ALL patients (mean +/- SEM was 102.8 +/- 6.3 microg/ml) as compared to normal controls (27.17 +/- 0.76 microg/ml), assay sensitivity being 91.3%. On an individual basis (n = 25) in patients who were longitudinally monitored for two years, a significant decline in their mean +/- SEM of OD405 was observed from 0.85 +/- 0.06 to 0.28 +/- 0.03. Additionally, a dot-blot was developed to evaluate the proportion of immune-complexed 9-OAcSGs in these patients employing achatinin-H, a 9-OAcSA-binding lectin. Our data indicate that these economically viable ELISA-based approaches allow for reliable, sensitive and rapid diagnosis of ALL. We contend that these disease-specific antibodies could be considered as potential markers both for the initial diagnosis of ALL and possibly for longitudinal monitoring of the disease.

Clinical Usefulness of the Hematopoietic Progenitor Cell Counts in Predicting the Optimal Timing of Peripheral Blood Stem Cell Harvest

Although enumeration of CD34+ cells in the peripheral blood (PB) on the day of apheresis predicts the quantity of those cells collected, the flow cytometric techniques used are complex and expensive, and several hours are required to obtain the result in the clinical practice setting. The Sysmex SE-9000 automated haematology analyzer provides an estimate of immature cells, called hematopoietic progenitor cells (HPC). The aim of this study was to evaluate the clinical usefulness of HPC in predicting the optimal timing of peripheral blood progenitor cells (PBPC) harvest. Studies were performed on 628 aphereses from 160 patients with hematologic or solid malignancies. Spearman's rank statistics was used to assess correlation between HPC, WBC, mononuclear cells (MNC), and CD34+ cells. A receiver operating characteristic (ROC) curve was drawn for cutoff value of HPC, and predictive values of the chosen cutoff value of HPC for different target CD34+ cell collections were calculated. The PB HPC had a stronger correlation (rho=0.592, por=1 x10(6)/kg with sensitivity of 75%. Positive and negative predictive values of HPC >or=50x10(6)/L for CD34+ cells >or=1x10(6)/kg were 59.7% and 81.1%, respectively. In the clinical practice setting, applying variable cutoff values of HPC would be a useful tool to predict the optimal timing of PBPC collection.

Quimioterapia preoperatoria en cáncer de mama / Preoperatory chemotherapy in breast cancer

El uso de la quimioterapia preoperatoria (Qx preop) en cáncer de mama localmente avanzado ha disminuido la tasa de pacientes consideradas inoperables y las recidivas locaes, aumentando según algunos la sobrevida libre de enfermedad y la sobrevida total. El objetivo de este trabajo es medir la respuesta del tumos de mama primario a la Qx preop y evaluar la influencia de ésta en la elección del tipo de tratamiento quirúrgico. Entre mayo de 1990 y marzo de 1995, ingresaron al protocolo de Qx preop del IOCPC, 93 pacientes con diagnóstico de cáncer de mama localmente avanzado, siendo evaluables para este estudio 80 pacientes. La Qx preop consistió en 3 ciclos de drogas con los esquemas de (CMF) o (FEC/FAC). La respuesta fue evaluada en comité oncológico al finalizar el tercer ciclo, en que se decidió la secuencia a seguir con el tratamiento, ya sea primero radioterapia (RT) o cirugía dependiendo de la respuesta clínica. La Qx preop tuvo una respuesta clínica completa o parcial en un 39 por ciento de las pacientes, permitiendo realizar un tratamiento conservador en un 16 por ciento de ellas. Con la adición de RT preoperatoria es posible reducir significativamente el número de pacientes consideradas inoperables en el momento de la evaluación inicial

Antitumor effects of rhodium (II) complexes on mice bearing Ehrlich tumors

Rhodium (II) trifluoracetate (TFARh), rhodium (II) trifluoracetate adduct with sulfadiazine (TFARh.Sd) and rhodium (II) acetate adduct with sulfisoxazole (RhSx) were tested in mice for acute toxicity, antitumoral activity against Ehrlich ascites carcinoma and for viability of Ehrlich tumor cells in culture. At ip doses up to 60 µmg/kg (40-70 and 59 mg/kg, respectively), these coumpounds had no toxic effects up to 14 days. At ip doses of 10 µmol Kg-1 day-1 for 5 days, TFARh and TFARh.Sd significantly increased the survival rate of mice bearing Ehrlich ascites cells (probability of survival to the end of 34th day, controls = 0.23, TFARh = 0.85, TFARh.Sd = 0.74). No significant effect was observed for RhSx. In vitro, these rhodium complexes at 40 µM significantly increased the number of dead cells in cultured Ehrlich tumor cells

Açäo de um esquema poliquimioterápico antineoplásico sobre a glicose e amilase sérica: provável acäo colateral sobre o tecido pancreático / Action of a antineoplastic polychemotherapy schedule on the glucose and serum amylase: probable collateral action on the pancreatic tissue

A discordância entre diagnóstico clínico e o resultado das análises laboratoriais tem sido uma constante no dia a dia da clínica médica. Esta situaçäo ficou esclarecida a partir dos trabalhos de CARAWAY (1962) que constatou a açäo interferente de medicamentos com poder de óxido reduçäo nos métodos de quantificaçäo da glicose e ácido úrico sérico, provocando um aumento sérico destes parâmetros bioquímicos. No presente trabalho, os resultados obtidos sugerem um açäo colateral sobre o tecido pancreático, constatada pelo aumento da glicose e amilase sérica quando pacientes com câncer de mama submeteram-se a poliquimioterapia antineoplástica constituída por metotrexate, fluoruracil e ciclosfosfamida

Modification of adriamycin-induced cytotoxicity by recombinant human interferon-gamma and/or verapamil in human stomach cancer cells

Recombinant human-interferon-gamma (rH-IFN-gamma) and verapamil (VRP), either alone or in combination, were evaluated in MTT assay for their modification effects on adriamycin-induced cytotoxicity against MKN-45, human stomach adenocarcinoma cells. VRP as a single agent did not inhibit the survival of MKN-45 at doses of up to 5.0 micrograms/ml. The survival of MKN-45 was inhibited by rH-IFN-gamma dose-dependently and further inhibited by the addition of VRP. However, the maximum growth inhibition of MKN-45 in any combination treatment with rH-IFN-gamma and VRP was less than 50% except in the highest concentration combinations (% survival: 47.9% at 10(4) U/ml of rH-IFN-gamma and 3.0 micrograms/ml of VRP). Adriamycin caused a concentration-dependent cytotoxicity and its cytotoxicity was significantly enhanced by the addition of rH-IFN-gamma and further enhanced by the combined use of rH-IFN-gamma and VRP. The modification effects of rH-IFN-gamma and VRP on adriamycin-induced cytotoxicity were evaluated in terms of modification index (MI), demonstrating that rH-IFN-gamma significantly increased in adriamycin-induced cytotoxicity and that the combined use of rH-IFN-gamma and VRP enhanced the adriamycin-induced cytotoxicity to a greater extent than did rH-IFN-gamma alone: MI values at 10(2) U/ml and 10(3) U/ml of rH-IFN-gamma were 1.7 and 3.1, respectively; those at 1.5 micrograms/ml and 3.0 micrograms/ml of VRP in the presence of 10(3) U/ml of rH-IFN-gamma were 4.4 and 6.0, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of adult acute myelogenous leukemia: a pilot study at Chulalongkorn Hospital.

Twenty-seven patients with acute myelogenous leukemia (AML), aged 15 to 65 years, were treated with standard induction remission chemotherapy and two different strategies for postremission treatment. Seventeen patients (63%) achieved complete remission (CR). Nine patients (37%) died during marrow hypoplasia. The median survival of complete remitters allocated to the intensive postremission therapy is projected to be in excess of 24 months with 53 per cent probability of remaining in CR at two years. The median remission duration for patients who entered the nonintensive postremission therapy was 11 months. Age was the major factor significantly correlated with the outcome of treatment. It is concluded that intensive curative treatment should be indicated in AML patients who are less than 30 years.

Quimioterapia del cáncer gástrico / Chemotherapy in gastric cancer

El cáncer gástrico se debe considerar una enfermedad sistémica, sin embargo, hasta ahora, no se cuenta con terapias eficaces para enfrentar esa situación. Hay varios fármacos que tienen actividad sobre la enfermedad (5 FU, Mitomicina C, Adriamicina, Nitrosoureas, Cis-platino, Etopósido, etc.) pero sus porcentajes de respuestas son bajos y por corto tiempo. En los últimos años la asociación de 5FU, Adriamicina y Mitomicina C ha sido desplazada por la combinación Etopósido, Adriamicina y Cis-platino (EAP). Este último esquema tendría un porcentaje de respuesta de 60% y con un 20% de respuestas completas. Hay evidencias además que apoyan el uso de la combinación de radioterapia con quimioterapia como complemento de la cirugía efectuada con criterio curativo y en pacientes con alto riesgo de recaídas. Finalmente los nuevos esquemas de poliquimioterapia ofrecen la posibilidad de hacer operables pacientes que por su extensión local fueron irresecables en una primera intervención. Se concluye que se estaría produciendo una probable mejoría en el manejo sistémico del cáncer gástrico

Antitumor effects of dopaminergic blockers in mice bearing ehrlich tumors

We determined the effect of 13 days of treatment with 2.0 mg/kg haloperidol, 30.0 mg/kg metoclopramide or 4.0 mg/kg domperidone on the number of tumor cells of mice bearing Ehrlich ascites carcinoma. The three dopaminergic blockers significantly reduced the number of tumor cells of experimental mice. The mean ñ SEM number of tumor cvells x 10******6/ml saline lavage was 25.5 ñ 5.9 for the haloperidol group, 36.8 ñ 4.7 for the metoclopramide group, 25.3 ñ 3.5 for the domperidone group and 54.0 ñ 9.0 for the control mice (treated with 0.9% NaCl). In a second experiment, treatment with 0.5 and 2.0 mg/kg haloperidol showed that the antitumor effect of this drug was dose dependent. The possible mechanisms underlying these results (such as an increase in prolactin levels or a direct action of these drugs on lymphocytes) are discussed in light of the specific pharmacological properties of each dopaminergic blocker

Actividad antitumoral del CCNU obtenido en Cuba / Antineoplasic activity of CCNU obtained in Cuba

El (1-[2-cloroetil] 1-nitroso, 3 ciclohexil urea) (CCNU) es una droga antitumoral que forma parte actualmente de múltiples esquemas de poliquimioterapia en el tratamienmto de diferentes localizaciones y su obtención en el país aumentará la disponibilidad de este producto. El presente trabajo evalúa la actividad, en comparación con el producto comercial usado actualmente en la clínica oncológica y por los resultados obtenidos en los tumores experimentales utilizados, ambos productos manifiestan semejante actividad antitumoral

Estabelecimento de um método "in vitro" de controle biológico de agentes antineoplásicos em uso no Instituto Nacional de Câncer

O objetivo do presente trabalho foi desenvolver um método capaz de verificar a eficácia, a nível biológico, das drogas antineoplásicas, que näo necessitem de metabolismo prévio para sua açäo e que atualmente estäo sendo usadas no Instituto Nacional de Câncer (INCa). O princípio de ensaio foi baseado na medida de inibiçäo da proliferaçäo celular da linhagem K562 e de células ativadas por fitohemaglutinina (PHA), usando-se como marcador a incorporaçäo no DNA de timidina tritiada. Conclui-se que esse ensaio näo é adequado para testar a atividade antitumoral do Methotrexate, mas pode ser extremamente sensível para os estudos com derivados da Vinca