Effect of Heat Shock Protein 72 Expression on Etoposide-induced Cell Death of Rat Retinal Ganglion Cells

PURPOSE: To assess whether the expression of heat shock protein 72 (Hsp72) protects rat retinal ganglion cells (RGC-5) from apoptotic cell death. METHODS: Hsp72 expression in RGC-5 cells transduced with replication-deficient recombinant adenovirus was analyzed by Western blot analysis and immunofluorescence. The effect of Hsp72 expression on etoposide-induced apoptotic cell death was examined by microscopic analysis and confirmed by cell proliferation assay. RESULTS: Western blot analysis and immunofluorescence clearly showed adenovirus-mediated Hsp72 expression in RGC-5 cells. Treatment with etoposide resulted in the death of a proportion of the cells by apoptosis. However, this apoptotic cell death was significantly reduced in cells expressing Hsp72, with the reduction in cell death correlating to the level of Hsp72 expression. CONCLUSIONS: Over-expression of Hsp72 alone is sufficient to rescue neuronal cells from apoptotic cell death, suggesting that fine-tuning its expression may be an effective neuroprotective approach in retinal degenerative disease.

Estudo de fase II com doses fracionadas diárias de etoposide oral em pacientes com câncer de mama estádio IV refratário a múltiplos esquemas quimioterápicos / Phase II study of fractionated daily doses of oral etoposide in patients with stage IV breast cancer refractory to multiple chemotherapy regimens

O etoposide é um inibidor da topoisomerase II capaz de produzir respostas objetivas em cerca de 10% das pacientes com câncer de mama metastático após a falha a esquemas convencionais. A administração oral de doses fracionadas de etoposide produz um aumento significativo do tempo de exposição dos tecidos em níveis terapêuticos deste agente, aumentando o seu índice terapêutico. Neste artigo, são descritos os resultados de um ensaio clínico de fase II com etoposide oral em doses fracionadas diárias em 20 mulheres com câncer de mama metastático refratário a múltiplos esquemas quimioterápicos. Foram elegíveis pacientes entre 18-75 anos de idade, desempenho clínico entre 0-2 (ECOG), diagnóstico histopatológico de câncer de mama, doença metastática visceral, sem disfunção de órgãosvitais e sem envolvimento do Sistema Nervoso Central (SNC). A assinatura de um documento de consentimento pelapaciente, segundo as normas da CONEP e do Comitê de Ética da Instituição, era condição necessária para inclusão.O conteúdo da ampola de etoposide para uso endovenoso foi administrado por via oral na dose de 20mg/m2 a cadaoito horas, diluído em veículo ácido (suco de laranja ou uva), diariamente por 14 dias, seguido de sete dias deintervalo. A cada 21 dias, as pacientes foram reavaliadas quanto à toxicidade (critério do NCI-CTC) e, a cada doisciclos (42 dias), quanto à resposta tumoral (critério da RECIST). As pacientes foram tratadas até a progressão, toxicidade limitante ou desejo próprio de interromper o tratamento. Foram incluídas 20 pacientes no estudo, tendo sido analisado um total de 55 ciclos de tratamento, com uma mediana de dois ciclos por paciente (1-10). Os efeitosadversos mais observados foram: náusea (36%), vômitos (24%), mucosite (16%) e neutropenia (14%). Neutropenia febril ocorreu em apenas um caso (2%). Não foram documentadas respostas objetivas. Entretanto, 9 pacientes apresentaram doença estável (45%), algumas com duração prolongada (30+, 21+ e...

Etoposide is an inhibitor of the nuclear topoisomerase II enzyme, which produces objective tumor responses inabout 10% of patients with metastatic breast cancer failing to standard chemotherapy regimens. Fractionatedoral administration of etoposide causes significant increase in tissue drug exposure, leading to a better therapeuticindex. In this paper, the outcomes of a Phase II trial of fractionated oral daily doses of etoposide conducted in20 women with metastatic breast cancer, who progressed following multiple chemotherapy regimens, are described. Eligible patients were those between 18-75 years old, ECOG performance status between 0-2, confirmed histopathological diagnosis of breast cancer, presence of visceral involvement, no vital organs dysfunction and no CNS involvement. A written informed consent was required, in accordance with the local IRB and theMinistry of Health of Brazil. The content of an ampoule for IV use was administered orally, at the dose of 20mg/m2, every eight hours, diluted in a low pH fluid (orange or grape juice), daily for 14 consecutive days,followed by a 7-day rest. Patients were reviewed every 21 days for toxicity (NCI-CTC criteria), and every 42days for tumoral response (RECIST criteria). Patients were treated until tumor progression, dose-limiting toxicityor own desire to interrupt the treatment. Twenty patients were included in the trial, and a total of 55 treatment cycles administered with a median of two cycles per patient (1-10) was evaluated. The most common side-effects were nausea (36%), vomiting (24%), mucositis (16%) and neutropenia (14%). Febrile neutropenia was documented in one case (2%) only. No objective response was documented. However, nine patients showed stable disease (45%), in some cases with prolonged duration (30+, 21+ and 18 weeks). The median duration of stable disease was 15 weeks (9-30+). In summary, this daily fractionated regimen of oral etoposide was welltolerated, producing...

Acute renal toxicity of 2 conditioning regimens in patients undergoing autologous peripheral blood stem-cell transplantation. Total body irradiation-cyclophosphamide versus ifosfamide, carboplatin, etoposide

To compare acute renal toxicity of 2 conditioning regimens of total body irradiation/cyclophosphamide TBI-Cy and Ifosfamide, Carboplatin, and Etoposide ICE. Between August 1996 and February 2004, patients treated with autologous peripheral stem cell transplantation in the Department of Medical and Radiation Oncology, Gulhane Military Medical School, Ankara, Turkey with 2 different conditioning regimens was comparatively analyzed for acute renal toxicity in the early post-transplant period. Forty-seven patients received ICE regimen with 12 g/m2; 1.2 g/m2; and 1.2 g/m2 divided to 6 consecutive days, whereas 21 patients received 12 Gy TBI 6 fractions twice daily in 3 consecutive days and 60 mg/m2/day cyclophosphamide for 2 days. Sixty-eight patients were evaluated in this study. There was no significant difference in baseline renal function between patients in the ICE and TBI-Cy groups. Eleven patients developed nephrotoxicity 23.4% in the ICE group while one patient 4.8% in the TBI-Cy group developed nephrotoxicity p=0.06. Five out of 11 patients developing nephrotoxicity in ICE group required hemodialysis and subsequently 4 8.5% of them died. In contrast, one patient 4.8% died due to nephrotoxicity despite hemodialysis in the TBI-Cy arm. This study reveals that the TBI-Cy conditioning regimen seems no more nephrotoxic than an ICE regimen particularly in patients who had used cisplatin prior to transplantation

Sequential chemoradiotherapy versus concurrent chemoradiotherapy plus consolidation chemotherapy in unresectable stage III non-small cell lung cancer

To evaluate the efficacy and toxicity of concurrent/consolidation chemoradiotherapy versus sequential chemoradiotherapy in unresectable stage III non-small cell lung cancer [NSCLC]. Between January 2003 and April 2006 thirty-two patients with stage III unresectable NSCLC were randomly assigned to one of the two treatment arms. In the sequential arm, patients received induction chemotherapy with docetaxel [75 mg/m[2]] repeated every 3 weeks for 3 cycles, followed by thoracic radiotherapy at a dose of 61Gy in 33 fractions over 6.5 weeks. In the concurrent/ consolidation arm, the same radiotherapy was started on day 2 with two concurrent cycles of cisplatin 50 mg/m2 on days 1, 8, 29, and 36; etoposide 50 mg/m2 on days 1 through 5 and 29 through 33. Then these patients received consolidation therapy with docetaxel started 4-6 weeks after concurrent chemoradiotherapy, repeated every 3 weeks for 3 cycles at a dose of 75 mg/m[2]. The overall response rate was higher in concurrent/consolidation arm [62.5%] than in sequential arm [43.7%], [P=0.03]. The median survival was 19 months in concurrent/ consolidation arm and 13.6 months in the sequential arm, [P=0.001]. The 2- year survival rate was better in concurrent/ consolidation arm [43.7%] than in the sequential arm [25%], [P=0.03]. Median progression-free survival was longer in concurrent/consolidation arm [11.9 months] than in sequential arm [8 months], [P=0.07]. The major and most frequent toxicity was neutropenia, which was 43.7% in concurrent/consolidation arm versus 56.2% in sequential arm, [P=0.09]. However, esophageal toxicity [>/= grade 3] was relatively higher in concurrent/consolidation arm 18.7% versus 6.2% in sequential arm, [P= 0.05]. Brain metastasis was the most common site of distant failure in both treatment arms. Locoregional failure was more frequent in sequential arm [37.5%] than in concurrent/consolidation arm [18.7%], [P=0.04]. Consolidation docetaxel after concurrent cisplatin/ etoposide with radiotherapy in stage III NSCLC was feasible, tolerable and can be safely administered with relatively low incidence of radiation esophagitis. In addition, treatment outcomes compared favorably with the sequential chemoradiotherapy

Cinética plasmática de uma microemulsão rica em colesterol (LDE) em pacientes com linfoma de Hodgkin e linfoma não-Hodgkin e estudo preliminar da toxicidade do etoposide associado à LDE / Plasma kinetics of a cholesterol-rich microemulsion (LDE) in patients with Hodgkin's and non-Hodgkin's lymphoma and a preliminary study on the toxicity of etoposide associated with LDE

Diminuição dos níveis da lipoproteína de baixa densidade (LDL) no plasma e da sua remoção plasmática é associada com neoplasias que apresentam aumento da expressão de receptores de LDL e pode permitir o uso da LDL ou de microemulsões ricas em colesterol (LDE) como veículos direcionadores de drogas contra células neoplásicas, uma modalidade de terapia-alvo.

Low plasma low-density lipoprotein (LDL) cholesterol and diminished LDL clearance is associated with cancers with upregulation of LDL receptors and may allow using LDL or cholesterol-rich microemulsions (LDE) as vehicles to target drugs against neoplastic cells. Our aim was to determine whether low LDL cholesterol concentration plus LDE increased clearance occur in lymphomas.

Tratamento sistêmico do sarcoma de Kaposi associado a AIDS: estudo clínico e farmacológico com doses fracionadas de etoposida por via oral / Treatment of AIDS related Kaposiïs sarcoma: clinical and pharmacological study with oral etoposide

Os objetivos deste estudo foram: avaliar a atividade antitumoral, a toxicidade e a farmacocinética da etoposida em doses orais fracionadas por um período de tempo prolongado em pacientes com Sarcoma de Kaposi avançado associado a AIDS; determinar o percentual de respostas objetivas alcançado pela etoposida na posologia proposta no estudo; estabelecer o perfil e a gravidade dos efeitos tóxicos apresentados pelos pacientes nesse esquema de administração da etoposida e descrever a farmacocinética da etoposida no plasma dos pacientes incluidos no estudo

Early results evaluating the efficacy and toxicity of adriamycin, vincristine and etoposide Ave in the management of childhood hodgkin's disease

This study aimed to evaluate efficacy and toxicity of adriamycin, vincristine and etoposide in the management of childhood Hodgkin's disease as a salvage and first line therapy as well as limiting the use of involved field radiotherapy to partial responders to avoid unnecessary complications of radiotherapy children. Thirty-six patients with Hodgkin's disease were included in this study, twenty- four had no previous treatment and twelve were previously treated with either C-MOPP or Chl-VPP [five of them had refractory disease and the remaining seven attained a complete remission but relapsed later]. All patients were treated with adriamycin 30 mg/m2, vincristine 1.4 mg/m2 and etoposide 100 mg/m2 D1 and D15 repeated every 28 days for six cycles. Partial responders [PR] were subjected to a field radiation treatment after three cycles of chemotherapy [20 Gy/ten treatments/two weeks]. At the end of the six cycles of chemotherapy, all patients were in a complete remission [CR]. All the previously untreated patients were in a complete remission after a median follow up of 15.5 months. The relapse free survival in previously treated patients was 58.3% after a median follow up of 14 months. The relapse free survival for the whole group was 86.7% after a median follow up of 15 months

Simposio. Avances recientes con ifosfamida/mesna en el tratamiento de tumores sólidos malignos: etopósido, platino, ifosfamida y dexametasona como tratamiento de rescate en los linfomas no Hodgkin / Symposium on recent advances with ifosfamide/Mesna in the treatment of malignant solid tumors

Existen grandes avances en el manejo de los linfomas; desafortunadamente un porcentaje variable de casos recaerán a regímenes de primera línea. Se informan los resultados preliminares de 17 pacientes con diagnóstico de linfoma de Hodgkin refractarios a manejo de primera línea o refractarios. El esquema utilizado fue cada 3-4 semanas: combinación de etopósido 100 mg/m² por tres días, platino 100 mg/m² e ifosfamida 5g/m² fraccionados en tres días, mesna al 20 por ciento de la dosis diaria de ifosfamida por tres dosis; y dexametasona de 20 a 40 mg cada 24 horas por tres días. Trece de los 17 pacientes fueron evaluables para eficacia (dos aún en tratamiento; los otros dos abandonaron la terapia) y 16 fueron evaluables para toxicidad en 74 ciclos administrados. Se obtuvieron 11 respuestas totales (84 por ciento): seis respuestas (46 por ciento) Äcon supervivencia libre de enfermedad mínima de dos meses y máxima de 11 mesesÄ y cinco respuestas parciales (38 por ciento). La toxicidad más frecuente y grave fue neutropenia grado 4 (20 por ciento) con dos muertos por septicemia y plaquetopenia grado 4 (7 por ciento). El resto de los efectos tóxicos fueron leves y reversibles. No se observó toxicidad vasical. Concluimos que el esquema utilizado es efectivo, pero conlleva toxicidad grave en una cuarta parte de los ciclos. Consideramos que es conveniente incluir factores estimulantes de colonias en este tratamiento