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1.
World Neurosurg ; 126: 624-630, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30599247

RESUMO

BACKGROUND: Pleomorphic xanthoastrocytoma (PXA) is categorized as grade II, other astrocytic tumors per the 2016 World Health Organization classification. Despite being a relatively benign type of tumor, PXA often has an aggressive clinical course. The more malignant form of PXA is now known as anaplastic pleomorphic xanthoastrocytoma (A-PXA) and is categorized as a grade III tumor. Clinical and genetic factors associated with malignant transformation remain unclear. In particular, typical genetic expression patterns in PXA and A-PXA remain unidentified. CASE DESCRIPTION: We present a case of recurrent PXA in which malignant transformation followed a promoter mutation in TERT. In this case, genetic chronologic changes accompanying malignant transformation of PXA were thoroughly examined. The promoter mutation was detected in the second operative specimen after stereotactic radiosurgery (SRS) at the first tumor recurrence. Subsequently, a malignant transformation to the A-PXA occurred at the time of the second recurrence, and the tumor repeatedly recurred afterward. CONCLUSIONS: TERT promotor mutations may contribute to the malignant transformation of PXA; the mechanism of this mutation is unknown, but it may have been caused by SRS. Therefore, improvident use of radiation should be avoided to prevent the malignant transformation of PXA.


Assuntos
Astrocitoma/genética , Neoplasias Encefálicas/genética , Transformação Celular Neoplásica/genética , Mutação , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas/genética , Telomerase/genética , Adulto , Antineoplásicos Alquilantes/uso terapêutico , Astrocitoma/tratamento farmacológico , Astrocitoma/patologia , Astrocitoma/cirurgia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Terapia Combinada , Inibidor de Quinase Dependente de Ciclina p15/genética , Procedimentos Cirúrgicos de Citorredução , Análise Mutacional de DNA , DNA de Neoplasias/genética , Feminino , Deleção de Genes , Genes p16 , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/cirurgia , Nimustina/uso terapêutico , Fotoquimioterapia , Porfirinas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Radiocirurgia , Reoperação , Lobo Temporal/patologia
2.
Neurology ; 90(19): e1673-e1681, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29643079

RESUMO

OBJECTIVE: We investigated whether cognitive performance between ages 43 and 69 years was associated with timing of menopause, controlling for hormone replacement therapy, childhood cognitive ability, and sociobehavioral factors. METHODS: We used data from 1,315 women participating in the Medical Research Council National Survey of Health and Development (a British birth cohort study) with known age at period cessation and up to 4 assessments of verbal memory (word-learning task) and processing speed (letter-cancellation task) at ages 43, 53, 60-64, and 69. We fitted multilevel models with linear and quadratic age terms, stratified by natural or surgical menopause, and adjusted for hormone replacement therapy, body mass index, smoking, occupational class, education, and childhood cognitive ability. RESULTS: Verbal memory increased with later age at natural menopause (0.17 words per year, 95% confidence interval [CI]: 0.07-0.27, p = 0.001); an association remained, albeit attenuated, after full adjustment (0.09, 95% CI: 0.02-0.17, p = 0.013). Verbal memory also increased with later age at surgical menopause (0.16, 95% CI: 0.06-0.27, p = 0.002), but this association was fully attenuated after adjustment. Search speed was not associated with age at menopause. CONCLUSION: Our findings suggest lifelong hormonal processes, not just short-term fluctuations during the menopause transition, may be associated with verbal memory, consistent with evidence from a variety of neurobiological studies; mechanisms are likely to involve estrogen receptor ß function. Further follow-up is required to assess fully the clinical significance of these associations.


Assuntos
Envelhecimento , Cognição/fisiologia , Menopausa , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Bleomicina , Estudos de Coortes , Ciclofosfamida , Citarabina , Doxorrubicina , Feminino , Humanos , Memória/fisiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Nimustina , Fatores Socioeconômicos , Reino Unido/epidemiologia , Aprendizagem Verbal/fisiologia
3.
J Cancer Res Ther ; 14(1): 78-83, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29516964

RESUMO

Background: Glioblastoma (GBM) is one of the worst cancers with bad prognosis despite systemic chemotherapy and radiotherapy after surgery. Methods: In this study, 71 patients with GBM were enrolled and randomly assigned to two groups: Receiving radiotherapy with concomitant and adjuvant temozolomide (TMZ) (TMZ, standard therapy) after surgery, or receiving radiotherapy with concomitant and adjuvant local delivery of nimustine (ACNU) rendezvousing with oral TMZ (rendezvous therapy). In the follow-up of all patients and the progression-free survival (PFS), overall survival (OS), Karnofsky performance score (KPS) and toxicities were recorded. Results: For the whole cohort, the median OS was 18.0 months, and the median PFS was 7.8 months. A significantly longer OS was observed in patients received rendezvous therapy than those who receiving standard therapy (18.5 months vs. 16.0 months; P = 0.014), as well as PFS (8.8 months vs. 7.0 months; P = 0.008). The KPS ≥70 rates were 81.8%, 40.9%, 20.5% in 1, 2, and 3 years for the rendezvous therapy group, significantly superior to standard therapy group. The most common toxicities were tolerable gastrointestinal reaction, liver dysfunction, and hematological toxicities, which were relieved with symptomatic treatment. Grade 3 or 4 toxicity was documented in 8 (18.3%) patients in rendezvous therapy group, while it was observed in 6 (22.2%) patients in standard therapy group during whole treatment process. Conclusions: Compared to standard therapy, the antitumor effects of rendezvous therapy were more effective in GBM patients without increasing the toxicities.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Radioterapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiorradioterapia , Terapia Combinada , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Feminino , Seguimentos , Glioblastoma/diagnóstico , Glioblastoma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Nimustina/administração & dosagem , Modelos de Riscos Proporcionais , Qualidade de Vida , Radioterapia/efeitos adversos , Radioterapia/métodos , Temozolomida , Tomografia Computadorizada por Raios X , Resultado do Tratamento
4.
JCO Clin Cancer Inform ; 2: 1-21, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30652567

RESUMO

PURPOSE: A major adverse effect arising from nimustine hydrochloride (ACNU) therapy for brain tumors is myelosuppression. Because its timing and severity vary among individual patients, the ACNU dose level has been adjusted in an empiric manner at individual medical facilities. To our knowledge, ours is the first study to develop a machine-learning approach to estimate myelosuppression through analysis of patient factors before treatment and attempts to clarify the relationship between myelosuppression and hematopoietic stem cells from daily clinical data. Adverse effect prediction will allow ACNU dose adjustment for patients predicted to have decreases in blood cell counts and will enable focused follow-up of patients undergoing chemoradiotherapy. PATIENTS AND METHODS: Patients were newly pathologically diagnosed with WHO grade 2 or 3 tumors and were treated with ACNU-based chemoradiotherapy. For detailed analysis of the timing and intensity of adverse effects in patients, we developed a data-weighted support vector machine (SVM) based on adverse event criteria (nadir-weighted SVM [NwSVM]). To evaluate the estimation accuracy of blood cell count dynamics, the determination coefficient ( r2) between real and estimated data was calculated by three regression methods: polynomial, SVM, and NwSVM. RESULTS: Only the NwSVM-based regression enabled estimation of the dynamics of all blood cell types with high accuracy (mean r2 = 0.81). The mean timing of nadir arrival estimated using this regression was 35 days for platelets, 41 days for RBCs, 52 days for lymphocytes, 57 days for WBCs, and 62 days for neutrophils. CONCLUSION: The NwSVM can be used to predict myelosuppression and clearly depicts nadir timing differences between platelets and other blood cells.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Leucopenia/diagnóstico , Aprendizado de Máquina , Modelos Estatísticos , Mielopoese/efeitos dos fármacos , Nimustina/efeitos adversos , Adulto , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Neoplasias Encefálicas/patologia , Feminino , Seguimentos , Humanos , Leucopenia/induzido quimicamente , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
5.
Exp Dermatol ; 27(1): 64-70, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28833504

RESUMO

Together with regulatory T cells (Tregs), tumor-associated macrophages (TAMs) play roles in maintaining the tumor microenvironment. Although cytotoxic antimelanoma drugs such as dacarbazine (DTIC), nimustine hydrochloride (ACNU) and vincristine (VCR) have been used for the treatment of malignant melanoma as adjuvant therapy in Japan, the detailed mechanisms of their immunomodulatory effects are not fully understood. As the majority of TAMs are alternatively activated M2 macrophages that favour tumor development, the aim of this study was to elucidate the immunomodulatory effects of these reagents on human monocyte-derived M2 macrophages. First, mRNA expressions and protein production of immune checkpoint molecules, PD-L1 and chemokines by CD163+ CD206+ M2 macrophages derived from peripheral blood mononuclear cells were investigated to determine the immunomodulatory effects of DTIC, ACNU, and VCR. DTIC and VCR significantly decreased PD-L1 mRNA expression, which was confirmed by flow cytometry. Moreover, the mRNA expression and production of CCL22 were significantly decreased by DTIC, which suggested that DTIC might suppress the recruitment of Tregs in the tumor site. Furthermore, the decreased expression of PD-L1 and production of CCL22 were validated in vivo, using the B16F10 mouse melanoma model, leading to abrogation of the suppressive function of T-cell proliferation. The present report suggests one of the possible antimelanoma mechanisms of DAV combination chemotherapy for melanoma patients.


Assuntos
Antineoplásicos/farmacologia , Macrófagos/efeitos dos fármacos , Melanoma/tratamento farmacológico , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígeno B7-H1/metabolismo , Dacarbazina/farmacologia , Feminino , Japão , Lectinas Tipo C/metabolismo , Leucócitos Mononucleares/metabolismo , Macrófagos/metabolismo , Lectinas de Ligação a Manose/metabolismo , Melanoma Experimental , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Nimustina/farmacologia , RNA Mensageiro/metabolismo , Receptores de Superfície Celular/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Vincristina/farmacologia
6.
Medicine (Baltimore) ; 96(41): e8218, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29019889

RESUMO

RATIONALE: Small cell lung cancer (SCLC) characterized by high degree of malignancy and rapid tumor progression. Intracranial metastases often appear at the time of the initial diagnosis or treatment. Besides of radiotherapy, chemotherapy is supposed to have limited effect. PATIENT CONCERNS: A 66-year-old male had blurred vision and unsteady step with moderate headache, nausea, vomit. DIAGNOSES: The patient was diagnosed with SCLC with intracranial metastases. INTERVENTIONS: High dose of nimustine (ACNU) (300 mg/m) add to the regimen containing carboplatin and irinotecan. OUTCOMES: Although the patient suffered severe myelosuppression, the intracranial lesion almost disappeared and maintained half a year. LESSONS: ACNU at a dose of 200 mg/m might be tolerable in combination with other chemotherapeutic drugs for the treatment of SCLC with intracranial metastases besides radiotherapy.


Assuntos
Neoplasias Encefálicas , Neoplasias Pulmonares/patologia , Nimustina , Carcinoma de Pequenas Células do Pulmão/patologia , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos Antineoplásicos , Encéfalo/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Relação Dose-Resposta a Droga , Humanos , Masculino , Estadiamento de Neoplasias , Exame Neurológico/métodos , Nimustina/administração & dosagem , Nimustina/efeitos adversos , Resultado do Tratamento , Transtornos da Visão/diagnóstico , Transtornos da Visão/etiologia
7.
Clin Cancer Res ; 23(22): 7020-7033, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28821557

RESUMO

Purpose: We aimed to characterize and target drug-tolerant BRCA1-deficient tumor cells that cause residual disease and subsequent tumor relapse.Experimental Design: We studied responses to various mono- and bifunctional alkylating agents in a genetically engineered mouse model for BRCA1/p53-mutant breast cancer. Because of the large intragenic deletion of the Brca1 gene, no restoration of BRCA1 function is possible, and therefore, no BRCA1-dependent acquired resistance occurs. To characterize the cell-cycle stage from which Brca1-/-;p53-/- mammary tumors arise after cisplatin treatment, we introduced the fluorescent ubiquitination-based cell-cycle indicator (FUCCI) construct into the tumor cells.Results: Despite repeated sensitivity to the MTD of platinum drugs, the Brca1-mutated mammary tumors are not eradicated, not even by a frequent dosing schedule. We show that relapse comes from single-nucleated cells delaying entry into the S-phase. Such slowly cycling cells, which are present within the drug-naïve tumors, are enriched in tumor remnants. Using the FUCCI construct, we identified nonfluorescent G0-like cells as the population most tolerant to platinum drugs. Intriguingly, these cells are more sensitive to the DNA-crosslinking agent nimustine, resulting in an increased number of multinucleated cells that lack clonogenicity. This is consistent with our in vivo finding that the nimustine MTD, among several alkylating agents, is the most effective in eradicating Brca1-mutated mouse mammary tumors.Conclusions: Our data show that targeting G0-like cells is crucial for the eradication of BRCA1/p53-deficient tumor cells. This can be achieved with selected alkylating agents such as nimustine. Clin Cancer Res; 23(22); 7020-33. ©2017 AACR.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Genes BRCA1 , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/genética , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Cisplatino/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Genes p53 , Humanos , Camundongos , Camundongos Knockout , Nimustina/farmacologia
8.
Acta Neurochir (Wien) ; 159(5): 939-946, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28247160

RESUMO

BACKGROUND: Convection-enhanced delivery (CED) is a technique allowing local infusion of therapeutic agents into the central nervous system, circumventing the blood-brain or spinal cord barrier. OBJECTIVE: To evaluate the utility of nimustine hydrochloride (ACNU) CED in controlling tumor progression in an experimental spinal cord glioma model. METHODS: Toxicity studies were performed in 42 rats following the administration of 4 µl of ACNU CED into the mid-thoracic spinal cord at concentrations ranging from 0.1 to 10 mg/ml. Behavioral analyses and histological evaluations were performed to assess ACNU toxicity in the spinal cord. A survival study was performed in 32 rats following the implantation of 9 L cells into the T8 spinal cord. Seven days after the implantation, rats were assigned to four groups: ACNU CED (0.25 mg/ml; n = 8); ACNU intravenous (i.v.) (0.4 mg; n = 8); saline CED (n = 8); saline i.v. (n = 8). Hind limb movements were evaluated daily in all rats for 21 days. Tumor sizes were measured histologically. RESULTS: The maximum tolerated ACNU concentration was 0.25 mg/ml. Preservation of hind limb motor function and tumor growth suppression was observed in the ACNU CED (0.25 mg/ml) and ACNU i.v. groups. Antitumor effects were more prominent in the ACNU CED group especially in behavioral analyses (P < 0.05; log-rank test). CONCLUSIONS: ACNU CED had efficacy in controlling tumor growth and preserving neurological function in an experimental spinal cord tumor model. ACNU CED can be a viable treatment option for spinal cord high-grade glioma.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Glioma/tratamento farmacológico , Nimustina/administração & dosagem , Neoplasias da Medula Espinal/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Convecção , Masculino , Nimustina/uso terapêutico , Ratos , Ratos Endogâmicos F344
9.
J Pathol ; 241(4): 511-521, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27943283

RESUMO

Women with heterozygous germline mutations in the BRCA1 tumour suppressor gene are strongly predisposed to developing early-onset breast cancer through loss of the remaining wild-type BRCA1 allele and inactivation of TP53. Although tumour prevention strategies in BRCA1-mutation carriers are still limited to prophylactic surgery, several therapeutic strategies have been developed to target the DNA repair defects (also known as 'BRCAness') of BRCA1-deficient tumours. In particular, DNA-damaging agents such as platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors show strong activity against BRCA1-mutated tumours. However, it is unclear whether drugs that target BRCAness can also be used to prevent tumour formation in BRCA1-mutation carriers, especially as loss of wild-type BRCA1 may not be the first event in BRCA1-associated tumourigenesis. We performed prophylactic treatments in a genetically engineered mouse model in which de novo development of BRCA1-deficient mammary tumours is induced by stochastic loss of BRCA1 and p53. We found that prophylactic window therapy with nimustine, cisplatin or olaparib reduced the amount and size of mammary gland lesions, and significantly increased the median tumour latency. Similar results were obtained with intermittent prophylactic treatment with olaparib. Importantly, prophylactic window therapy with nimustine and cisplatin resulted in an increased fraction of BRCA1-proficient mammary tumours, suggesting selective survival and malignant transformation of BRCA1-proficient lesions upon prophylactic treatment with DNA-damaging agents. Prophylactic therapy with olaparib significantly prolonged mammary tumour-free survival without any significant increase in the fraction of BRCA1-proficient tumours, warranting the evaluation of this PARP inhibitor in prophylactic trials in BRCA1-mutation carriers. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Proteínas Supressoras de Tumor/genética , Animais , Antineoplásicos/uso terapêutico , Proteína BRCA1 , Cisplatino/farmacologia , Reparo do DNA , Modelos Animais de Doenças , Feminino , Mutação em Linhagem Germinativa , Humanos , Neoplasias Mamárias Animais/patologia , Neoplasias Mamárias Animais/prevenção & controle , Camundongos , Nimustina/farmacologia , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Supressoras de Tumor/metabolismo
10.
Artigo em Inglês | MEDLINE | ID: mdl-27599192

RESUMO

A new method to evaluate the anticancer activity at the molecular level has been developed. In our assay, the interaction between alkylating anticancer drugs-Fe3O4/CA with DNA has been investigated for the Resonance Light Scattering (RLS) signal enhancement. Water-based nano-Fe3O4, as a probe, has the ability of good solubility, biodegradability and low bulk resistivity etc. The experimental results show that, the activity order of three kinds of drugs is Nimustine (ACNU)>Semustine (Me-CCNU)>Chlormethine (HN2), which is satisfied with the results of the cell apoptosis experiment and the IC50 by MTT method. This assay is simple, sensitive and high efficient. And the theoretical basics for the development of new anticancer drugs as well as the assessments of their efficacy to cure breast and hepatic cancer have been provided.


Assuntos
Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacologia , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Nanopartículas Metálicas/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ácido Cítrico/química , DNA/química , DNA/metabolismo , Portadores de Fármacos/farmacologia , Feminino , Compostos Férricos/química , Humanos , Concentração Inibidora 50 , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Células MCF-7 , Nimustina/farmacologia , Semustina/farmacologia , Espectrofotometria Infravermelho , Viscosidade
11.
Neurol Med Chir (Tokyo) ; 57(1): 17-27, 2017 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-27725524

RESUMO

The objective of this phase I/II study was to examine the efficacy and toxicity profile of temozolomide (TMZ) plus nimustine (ACNU). Patients who had received a standard radiotherapy with one or two previous chemo-regimens were enrolled. In phase I, the maximum-tolerated dose (MTD) by TMZ (150 mg/m2/day) (Day 1-5) plus various doses of ACNU (30, 35, 40, 45 mg/m2/day) (Day 15) per 4 weeks was defined on a standard 3 + 3 design. In phase II, these therapeutic activity and safety of this regimen were evaluated. Forty-nine eligible patients were enrolled. The median age was 50 years-old. Eighty percent had a KPS of 70-100. Histologies were glioblastoma (73%), anaplastic astrocytoma (22%), anaplastic oligodendroglioma (4%). In phase I, 15 patients were treated at four cohorts by TMZ plus ACNU. MTD was TMZ (150 mg/m2) plus ACNU (40 mg/m2). In phase II, 40 patients were treated at the dose of cohort 3 (MTD). Thirty-five percent of patients experienced grade 3 or 4 toxicities, mainly hematologic. The overall response rate was 11% (4/37). Sixty-eight percent (25/37) had stable disease. Twenty-two percent (8/37) showed progression. Progression-free survival (PFS) rates at 6 and 12 months were 24% (95% CI, 12-35%) and 8% (95% CI, 4-15%). Median PFS was 13 months (95% CI, 9.2-17.2 months). Overall survival (OS) at 6 and 12 were 78% (95% CI, 67-89%) and 49% (95% CI, 33-57%). Median OS was 11.8 months (95% CI, 8.2-14.5 months). This phase I/II study showed a moderate toxicity in hematology and may has a promising efficacy in OS, without inferiority in PFS.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Glioma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Nimustina/uso terapêutico , Adulto , Idoso , Dacarbazina/uso terapêutico , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Temozolomida
12.
J Med Case Rep ; 10(1): 284, 2016 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-27756356

RESUMO

BACKGROUND: Oral mucosal melanoma is a rare disease with a relatively poor prognosis. Carbon ion radiotherapy has been shown to be effective against radiotherapy-resistant tumors owing to its excellent dose concentration and high biological effect. CASE PRESENTATION: Our patient was a 66-year-old Japanese man with oral mucosal melanoma of his right maxillary gingiva (T4aN0M0). He received carbon ion radiotherapy at 57.6 Gy (relative biological effectiveness) in 16 fractions for 4 weeks. Concomitant chemotherapy (dacarbazine + nimustine + vincristine) was administered at the same time as carbon ion radiotherapy initiation. Two courses of adjuvant chemotherapy were given after carbon ion radiotherapy. Although he experienced grade 2 acute oral mucositis, his symptoms improved within a few weeks of undergoing carbon ion radiotherapy. He was alive at the time of reporting, 35 months after treatment, without any recurrence. Late toxicity has not been observed. CONCLUSIONS: Carbon ion radiotherapy for oral mucosal melanoma resulted in a good local effect.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Radioterapia com Íons Pesados , Melanoma/radioterapia , Mucosa Bucal/patologia , Neoplasias Bucais/radioterapia , Recidiva Local de Neoplasia/prevenção & controle , Lesões por Radiação/patologia , Idoso , Terapia Combinada , Dacarbazina/administração & dosagem , Radioterapia com Íons Pesados/efeitos adversos , Radioterapia com Íons Pesados/métodos , Humanos , Masculino , Melanoma/patologia , Mucosa Bucal/efeitos da radiação , Neoplasias Bucais/patologia , Membrana Mucosa/patologia , Membrana Mucosa/efeitos da radiação , Nimustina/administração & dosagem , Dosagem Radioterapêutica , Resultado do Tratamento , Vincristina/administração & dosagem
13.
Cancer Med ; 5(11): 3147-3155, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27734611

RESUMO

Nimustine (ACNU) has antitumor activities in patients with malignant glioma. Hyperbaric oxygen (HBO) may enhance the efficacy of certain therapies that are hampered by the hypoxic microenvironment. We examined the combined effects of ACNU and HBO in a GFP transgenic nude mice bearing human glioma model. Mice inoculated with human glioma cells SU3 were randomly divided into the four groups: (A) the control group, (B) the HBOT (HBO therapy) group, (C) the ACNU group, and (D) the HBOT+ACNU group. Tumor size was measured at the indicated time intervals with a caliper; mice were sacrificed 28 days after treatment, and immunohistochemistry staining and western blot analysis were carried out. By the end of the trial, the tumor weights of groups A, B, C, and D were (P < 0.05), 6.03 ± 1.47, 4.13 ± 1.82 (P < 0.05), 2.39 ± 0.25 (P < 0.05), and 1.43 ± 0.38 (P < 0.01), respectively. The expressions of TNF-α, MMP9, HIF-α, VEGF, NF-κB, and IL-1ß were associated with the infiltration of inflammatory cells and the inhibition rate of tumor cells. Hyperbaric oxygen therapy (HBOT) could inhibit glioma cell proliferation and inflammatory cell infiltration, and exert a sensitizing effect on ACNU therapy partially through enhancing oxygen pressure (PO2 ) in tumor tissues and lower expression levels of HIF-1α, TNF-α, IL-1ß, VEGF, MMP9, and NF-κB.


Assuntos
Antineoplásicos/farmacologia , Glioma/metabolismo , Glioma/patologia , Oxigenação Hiperbárica , Nimustina/farmacologia , Animais , Biomarcadores , Peso Corporal , Linhagem Celular Tumoral , Modelos Animais de Doenças , Glioma/mortalidade , Glioma/terapia , Humanos , Oxigenação Hiperbárica/métodos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Transgênicos , Modelos Biológicos , NF-kappa B/metabolismo , Transdução de Sinais , Carga Tumoral , Fator de Necrose Tumoral alfa/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Neurooncol ; 130(1): 165-170, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27535747

RESUMO

To evaluate the safety and efficacy of postoperative proton beam therapy (PBT) combined with nimustine hydrochloride (ACNU) or temozolomide (TMZ) for glioblastoma multiforme (GBM). The subjects were 46 patients with GBM who were treated with high dose (96.6 GyE) PBT. There were 24 males and 22 females, and the median age was 58 years old (range 24-76). The Karnofsky performance status was 60, 70, 80, 90 and 100 in 5, 10, 12, 11 and 8 patients, respectively. Total resection, partial resection, and biopsy were performed for 31, 14 and 1 patients, respectively. Photon beams were delivered to high intensity areas on T2-weighted magnetic resonance imaging (MRI) in the morning (50.4 Gy in 28 fractions). More than 6 h later, PBT was delivered to the enhanced area plus a 10 mm margin in the first half of the protocol (23.1 GyE in 14 fractions) and to the enhanced volume in the second half (23.1 GyE in 14 fraction). Concurrent chemotherapy with ACNU during weeks 1 and 4 or daily TMZ was administered in 23 and 23 patients, respectively. The overall 1 and 2 year survival rates were 82.6 and 47.6 %, respectively. Median survival was 21.1 months (95 % CI 13.1-29.2), with no significant difference in survival between the ACNU and TMZ groups. The patient characteristics were similar in the two groups. Late radiation necrosis occurred in 11 patients (six ACNU, five TMZ), but was controlled by necrotomy and therapy including bevacizumab. PBT concurrent with ACNU or TMZ was tolerable and beneficial for carefully selected patients with GBM.


Assuntos
Antineoplásicos/uso terapêutico , Dacarbazina/análogos & derivados , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Nimustina/uso terapêutico , Terapia com Prótons/métodos , Adulto , Idoso , Dacarbazina/uso terapêutico , Feminino , Seguimentos , Glioblastoma/diagnóstico por imagem , Glioblastoma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Temozolomida , Resultado do Tratamento , Adulto Jovem
15.
J Natl Cancer Inst ; 108(11)2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27381626

RESUMO

BACKGROUND: Although BRCA1-deficient tumors are extremely sensitive to DNA-damaging drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, recurrences do occur and, consequently, resistance to therapy remains a serious clinical problem. To study the underlying mechanisms, we induced therapy resistance in patient-derived xenograft (PDX) models of BRCA1-mutated and BRCA1-methylated triple-negative breast cancer. METHODS: A cohort of 75 mice carrying BRCA1-deficient breast PDX tumors was treated with cisplatin, melphalan, nimustine, or olaparib, and treatment sensitivity was determined. In tumors that acquired therapy resistance, BRCA1 expression was investigated using quantitative real-time polymerase chain reaction and immunoblotting. Next-generation sequencing, methylation-specific multiplex ligation-dependent probe amplification (MLPA) and Target Locus Amplification (TLA)-based sequencing were used to determine mechanisms of BRCA1 re-expression in therapy-resistant tumors. RESULTS: BRCA1 protein was not detected in therapy-sensitive tumors but was found in 31 out of 42 resistant cases. Apart from previously described mechanisms involving BRCA1-intragenic deletions and loss of BRCA1 promoter hypermethylation, a novel resistance mechanism was identified in four out of seven BRCA1-methylated PDX tumors that re-expressed BRCA1 but retained BRCA1 promoter hypermethylation. In these tumors, we found de novo gene fusions that placed BRCA1 under the transcriptional control of a heterologous promoter, resulting in re-expression of BRCA1 and acquisition of therapy resistance. CONCLUSIONS: In addition to previously described clinically relevant resistance mechanisms in BRCA1-deficient tumors, we describe a novel resistance mechanism in BRCA1-methylated PDX tumors involving de novo rearrangements at the BRCA1 locus, demonstrating that BRCA1-methylated breast cancers may acquire therapy resistance via both epigenetic and genetic mechanisms.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Fusão Gênica , Genes BRCA1 , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Animais , Proteína BRCA1/deficiência , Cisplatino/uso terapêutico , Metilação de DNA , Feminino , Expressão Gênica , Humanos , Melfalan/uso terapêutico , Camundongos , Mutação , Transplante de Neoplasias , Nimustina/uso terapêutico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Regiões Promotoras Genéticas
16.
Oncotarget ; 7(42): 69002-69013, 2016 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-27458167

RESUMO

Different chemotherapy drugs are generally introduced in clinical practices combining with therapy for glioma treatment. However, these chemotherapy drugs have rarely been compared with each other and the optimum drug still remains to be proved. In this research, medical databases were consulted, PubMed, Embase and Cochrane Library included. As primary outcomes, hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS) with their corresponding 95% credential intervals (CrI) were reported. A network meta-analysis was conducted; the surface under the cumulative ranking curve (SUCRA) was utilized for treatment rank and a cluster analysis based on SUCRA values was performed. This research includes 14 trials with 3,681 subjects and eight interventions. In terms of network meta-analysis, placebo was proved to be inferior to the combination of temozolomide (TMZ), nimustine (ACNU) and cisplatin (CDDP). Also, bevacizumab (BEV) in conjunction with TMZ were significantly more effective than placebo with an HR of 0.40. The estimated probabilities from SUCRA verified the above outcomes, confirming that the combination of TMZ, ACNU and CDDP exhibited the highest ranking probability of 0.889 with respect to OS, while BEV in combination with TMZ - with a probability of 0.772 - ranked the first place with respect to PFS. According to the results of this network meta-analysis, the combination of (1) TMZ, ACNU and CDDP; (2) BEV in combination with TMZ and (3) cilengitide in combination with TMZ, are considered as the preferable choices of chemotherapy drugs for glioma treatment.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Glioma/terapia , Anticorpos Monoclonais Humanizados , Antineoplásicos/administração & dosagem , Teorema de Bayes , Bevacizumab/administração & dosagem , Neoplasias Encefálicas/mortalidade , Cisplatino/administração & dosagem , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Intervalo Livre de Doença , Eflornitina/administração & dosagem , Glioma/mortalidade , Humanos , Mitolactol/administração & dosagem , Metanálise em Rede , Nimustina/administração & dosagem , Probabilidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Venenos de Serpentes/administração & dosagem , Temozolomida , Resultado do Tratamento , Vincristina/administração & dosagem
17.
PLoS One ; 11(3): e0152407, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27014877

RESUMO

Radiation therapy is an important treatment choice for unresectable advanced human lung cancers, and a critical adjuvant treatment for surgery. However, radiation as a lung cancer treatment remains far from satisfactory due to problems associated with radiation resistance in cancer cells and severe cytotoxicity to non-cancer cells, which arise at doses typically administered to patients. We have recently identified a promising novel inhibitor of ß-catenin/Tcf4 interaction, named BC-23 (C21H14ClN3O4S), which acts as a potent cell death enhancer when used in combination with radiation. Sequential exposure of human p53-null non-small cell lung cancer (NSCLC) H1299 cells to low doses of x-ray radiation, followed 1 hour later by administration of minimally cytotoxic concentrations of BC-23, resulted in a highly synergistic induction of clonogenic cell death (combination index <1.0). Co-treatment with BC-23 at low concentrations effectively inhibits Wnt/ß-catenin signaling and down-regulates c-Myc and cyclin D1 expression. S phase arrest and ROS generation are also involved in the enhancement of radiation effectiveness mediated by BC-23. BC-23 therefore represents a promising new class of radiation enhancer.


Assuntos
Antineoplásicos/química , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Nimustina/química , Tolerância a Radiação/efeitos dos fármacos , Fatores de Transcrição/metabolismo , beta Catenina/metabolismo , Ligação Competitiva , Carcinoma Pulmonar de Células não Pequenas/terapia , Ciclo Celular , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos da radiação , Ciclina D1/metabolismo , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Luciferases/metabolismo , Neoplasias Pulmonares/terapia , Células-Tronco Neoplásicas/citologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Espectrometria de Fluorescência , Fator de Transcrição 4 , Raios X
19.
Oncotarget ; 6(32): 33755-68, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26418950

RESUMO

The outcome of cancer therapy strongly depends on the complex network of cell signaling pathways, including transcription factor activation following drug exposure. Here we assessed whether and how the MAP kinase (MAPK) cascade and its downstream target, the transcription factor AP-1, influence the sensitivity of malignant glioma cells to the anticancer drugs temozolomide (TMZ) and nimustine (ACNU). Both drugs induce apoptosis in glioma cells at late times following treatment. Activation of the MAPK cascade precedes apoptosis, as shown by phosphorylation of Jun kinase (JNK) and c-Jun, a main component of AP-1. Pharmacological inhibition and siRNA mediated knockdown of JNK and c-Jun reduced the level of apoptosis in LN-229 glioma cells treated with TMZ or ACNU. Analyzing the underlying molecular mechanism, we identified the pro-apoptotic gene BIM as a critical target of AP-1, which is upregulated following TMZ and ACNU. Importantly, shRNA mediated downregulation of BIM in the malignant glioma cell lines LN-229 and U87MG led to an attenuated cleavage of caspase-9 and, consequently, reduced the level of apoptosis following TMZ and ACNU treatment. Overall, we identified JNK/c-Jun activation and BIM induction as a late pro-apoptotic response of glioma cells treated with alkylating anticancer drugs.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose , Dacarbazina/análogos & derivados , Glioblastoma/patologia , MAP Quinase Quinase 4/metabolismo , Proteínas de Membrana/metabolismo , Nimustina/farmacologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Antineoplásicos Alquilantes/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína 11 Semelhante a Bcl-2 , Linhagem Celular Tumoral/efeitos dos fármacos , Núcleo Celular/metabolismo , Ensaio Cometa , Dacarbazina/farmacologia , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases , Fosforilação , Estrutura Terciária de Proteína , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Temozolomida , Regulação para Cima
20.
Int J Biol Macromol ; 81: 891-7, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26391598

RESUMO

We report surface-enhanced Raman spectroscopic (SERS) studies on free calf thymus DNA and its complexes with anti-tumor chloroethyl nitrosourea derivatives; semustine and nimustine. Since, first incident of SERS in 1974, it has rapidly established into an analytical tool, which can be used for the trace detection and characterization of analytes. Here, we depict yet another application of SERS in the field of drug-DNA interaction and thereby, its promising role in rational designing of new chemotherapeutic agents. Vibrational spectral analysis has been performed in an attempt to delineate the anti-cancer action mechanism of above mentioned nitrosourea derivatives. Strong SERS bands associated with the complexation of DNA with semustine and nimustine have been observed, which reveal binding of nitrosourea derivatives with heterocyclic nitrogenous base pair of DNA duplex. Formation of dG-dC interstrand cross-link in DNA double helices is also suggested by the SERS spectral outcomes of CENUs-DNA adduct. Results, demonstrated here, reflect recent progress in the newly developing field of drug-DNA interaction analysis via SERS.


Assuntos
DNA/química , Nimustina/química , Semustina/química , Análise Espectral Raman/métodos , Animais , Bovinos , Coloides , Nanopartículas Metálicas/química , Prata/química , Espectrofotometria Ultravioleta
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