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1.
Dalton Trans ; 41(21): 6396-8, 2012 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-22415445

RESUMO

The conjugation of a ferrocenyl amino acid to the cell-penetrating peptide hCT(9-32) does not impair its ability to efficiently translocate into cells. Furthermore, the bioconjugate does not induce any cytotoxicity, thus presenting a potential electrochemical sensor suitable for the detection of living cells.


Assuntos
Aminoácidos/química , Aminoácidos/metabolismo , Técnicas Biossensoriais/métodos , Peptídeos Penetradores de Células/metabolismo , Compostos Ferrosos/química , Sobrevivência Celular , Eletroquímica , Células HeLa , Humanos , Metalocenos
2.
J Cancer Res Clin Oncol ; 137(4): 639-49, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20544219

RESUMO

PURPOSE: Due to the severe problems accompanied with multiple drug resistance (MDR), agents that can induce apoptosis independently of death-suppressing proteins are required. Here, we show that the ferrocene derivative HUNI 068 is active against cancer cells and overcomes different mechanisms of multiple drug resistance (MDR). METHODS: Proliferation inhibition was determined by using a CASY(®)CellCounter. DNA fragmentation assay and annexin-V/PI binding assays measured apoptosis, and necrosis was excluded by LDH-release assay. Drug-resistant cell lines were generated to test the ability to overcome MDR. By real-time PCR, alterations in gene expression of treated cells were analyzed. The apoptosis pathway was investigated by immunoblotting and measurement of mitochondrial membrane permeability transition. RESULTS: HUNI 068 leads to proliferation inhibition and apoptosis mediation, but only minimal necrosis induction. Healthy leukocytes seem to be less affected than cancer cells. The compound overcomes drug resistance to vincristine and daunorubicin. Independence of p-glycoprotein and Bcl-2 overexpression is probable, and upregulation of the anti-Bcl-2 protein harakiri was seen. Combined treatment with vincristine leads to synergistic effects. In different primary tumor cells, HUNI 068 achieved acceptable effects where tolerance to some conventional drugs was shown. Induction of apoptosis is FADD-independent, but associated with a reduced mitochondrial membrane potential and activation of caspase-9, indicating the intrinsic apoptosis pathway via mitochondria. CONCLUSIONS: HUNI 068 is a promising new compound with activity even against MDR tumor cells. Further investigations into the class of ferrocene-derived agents might reveal compounds with improved activity for a more specific and safe anti-cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Ferrosos/farmacologia , Succinatos/farmacologia , Caspase 9/metabolismo , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Metalocenos , Vincristina/farmacologia
3.
Pediatr Blood Cancer ; 52(5): 677-9, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19127572

RESUMO

We report a 12-year-old female presenting with an abdominal tumor. Diagnostic workup revealed giant bilateral ovarian cysts, severe hypothyroidism as well as an elevation of CA 125. We refrained from ovariectomy, which would be necessary for a malignant tumor, in view of an evident Van Wyk and Grumbach syndrome. The patient promptly responded to L-thyroxine with complete regression of all symptoms. Hypothyroidism should be considered in the evaluation of ovarian cysts. Although the Van Wyk and Grumbach syndrome is rare, it is crucial to rule it out in order to avoid unnecessary ovarian surgery when thyroid replacement is completely sufficient.


Assuntos
Hipotireoidismo/complicações , Hipotireoidismo/patologia , Cistos Ovarianos/complicações , Cistos Ovarianos/patologia , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/patologia , Criança , Feminino , Humanos , Hipotireoidismo/sangue , Hipotireoidismo/tratamento farmacológico , Imageamento por Ressonância Magnética , Cistos Ovarianos/tratamento farmacológico , Cistos Ovarianos/cirurgia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Ovariectomia , Síndrome , Tiroxina/uso terapêutico
4.
J Clin Oncol ; 26(27): 4385-93, 2008 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-18802150

RESUMO

PURPOSE: The European Intergroup Cooperative Ewing's Sarcoma Study investigated whether cyclophosphamide has a similar efficacy as ifosfamide in standard-risk (SR) patients and whether the addition of etoposide improves survival in high-risk (HR) patients. PATIENTS AND METHODS: SR patients (localized tumors, volume <100 mL) were randomly assigned to receive four courses of vincristine, dactinomycin, ifosfamide, and doxorubicin (VAIA) induction therapy followed by 10 courses of either VAIA or vincristine, dactinomycin, cyclophosphamide, and doxorubicin (VACA; cyclophosphamide replacing ifosfamide). HR patients (volume >or=100 mL or metastases) were randomly assigned to receive 14 courses of either VAIA or VAIA plus etoposide (EVAIA). Outcome measures were event-free survival (EFS; defined as the time to first recurrence, progression, second malignancy, or death) and overall survival (OS). RESULTS: A total of 647 patients were randomly assigned: 79 SR patients were assigned to VAIA, 76 SR patients were assigned to VACA, 240 HR were assigned to VAIA, and 252 HR patients were assigned to EVAIA. The median follow-up was 8.5 years. In the SR group, the hazard ratios (VACA v VAIA) for EFS and OS were 0.91 (95% CI, 0.55 to 1.53) and 1.08 (95% CI, 0.58 to 2.03), respectively. There was a higher incidence of hematologic toxicities in the VACA arm. In the HR group, the EFS and OS hazard ratios (EVAIA v VAIA) indicated a 17% reduction in the risk of an event (95% CI, -35% to 5%; P = .12) and 15% reduction in dying (95% CI, -34% to 10%), respectively. The effect seemed greater among patients without metastases (hazard ratio = 0.79; P = .16) than among those with metastases (hazard ratio = 0.96; P = .84). CONCLUSION: Cyclophosphamide seemed to have a similar effect on EFS and OS as ifosfamide in SR patients but was associated with increased toxicity. In HR patients, the addition of etoposide seemed to be beneficial.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Etoposídeo/administração & dosagem , Ifosfamida/administração & dosagem , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/patologia , Criança , Pré-Escolar , Terapia Combinada , Dactinomicina/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Doenças Hematológicas/induzido quimicamente , Humanos , Lactente , Neoplasias Pulmonares/secundário , Masculino , Estadiamento de Neoplasias , Estudos Prospectivos , Sarcoma de Ewing/patologia , Sarcoma de Ewing/secundário , Vincristina/administração & dosagem
5.
Pediatr Blood Cancer ; 47(6): 795-800, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16411206

RESUMO

BACKGROUND: The prognosis of Ewing tumor (ET) patients has significantly improved to cure rates approximating 70%. The prognosis in relapse, however, is poor. Promising response rates have recently been reported for the combination of topotecan (TOPO) and cyclophosphamide (CYC) encouraging wider application of this combination in patients with relapsed ETs. This report summarizes the experience of patients treated with TOPO/CYC for recurrent or refractory disease within the German ET trials. PROCEDURE: Fifty-four patients aged 3.2-49.5 (median: 17.4) years received TOPO (0.75 mg/m2/day, days 1-5) and CYC (250 mg/m2/day, days 1-5) following first (40) or second (6) relapse or progression under first-line therapy (8). RESULTS: A median of 3 (range: 1-11) TOPO/CYC courses were given. Sixteen patients (32.6%) showed partial response (PR), 13/49 (26.5%) had stable disease (SD), 14/49 (28.6%) progressed, 2/49 (4.1%) showed a mixed response (MR). In 4 patients response was not documented, 5/54 patients with complete initial resection at the diagnosis of relapse were excluded from the response analysis. At completion of relapse therapy, 24/54 patients had entered complete (19) or partial (5) remission, 2 had SD, 26 showed progression, information was unavailable in 2 patients. Of the 19 relapse patients achieving complete response (CR), 10 maintained remission (52.6%). At the time of evaluation, after a median follow-up for survivors of 23.1 (range: 7.8-59.8) months from the event prompting TOPO/CYC treatment, 14/54 patients (25.9%) were in continuous complete (13) or partial (1) remission. Overall survival (OAS) after 1 year was 0.61 (95%-CI 0.47-0.74). CONCLUSION: TOPO/CYC is active in relapsed ETs and warrants further evaluation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Topotecan/administração & dosagem , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/diagnóstico , Criança , Pré-Escolar , Ciclofosfamida/efeitos adversos , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Prognóstico , Recidiva , Indução de Remissão , Terapia de Salvação , Sarcoma de Ewing/diagnóstico , Taxa de Sobrevida , Topotecan/efeitos adversos , Resultado do Tratamento
6.
Int J Radiat Oncol Biol Phys ; 63(5): 1562-7, 2005 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16137838

RESUMO

PURPOSE: Treatment results in patients with Ewing tumors of the vertebrae enrolled in the Cooperative Ewing's Sarcoma Study (CESS) 81, 86, and the European Intergroup Cooperative Ewing's Sarcoma Study (EICESS) 92 trials were analyzed with special emphasis on radiation-associated factors. PATIENTS AND METHODS: A retrospective analysis was performed on 116 patients with primary tumors of the cervical, thoracic, or lumbar vertebrae treated between 1981 and 1999. Furthermore, a relapse analysis was done on those patients who underwent radiotherapy and subsequently had a local recurrence. RESULTS: A total of 64.6% of the patients received definitive radiotherapy; 27.5% of patients had surgery and radiotherapy. Only 4 patients (3.4%) underwent definitive surgery. Twenty-seven patients presented with metastases at diagnosis. 22.4% of the total group developed a local relapse. Among the subgroup with definitive radiotherapy, local recurrence was seen in 17 of 75 patients (22.6%). Event-free survival and survival at 5 years were 47% and 58%, respectively. Of the 14 evaluable patients with a local relapse after radiotherapy, 13 were in-field. No correlation between radiation dose and local control could be found. CONCLUSION: Surgery with wide resection margins is rarely possible. The results after definitive radiotherapy in vertebral tumors are comparable to those of other tumor sites when definitive radiotherapy is given. Nearly all local relapses after radiotherapy are in-field.


Assuntos
Sarcoma de Ewing/radioterapia , Neoplasias da Coluna Vertebral/radioterapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia , Radioterapia/efeitos adversos , Estudos Retrospectivos , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/cirurgia , Neoplasias da Coluna Vertebral/tratamento farmacológico , Neoplasias da Coluna Vertebral/cirurgia , Resultado do Tratamento
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