RESUMO
The high malignancy of glioblastoma has been recently attributed to the presence, within the tumor, of glioblastoma stem cells (GSC) poorly responsive to chemo- and radiotherapy. Here, the potential employment of metformin and arsenic trioxide (ATO) in glioblastoma therapy is discussed focusing on their effects on GSC. Metformin exerts anticancer effects by primarily blocking the pivotal LKB1/AMPK/mTOR/S6K1 pathway-dependent cell growth, induces selective lethal effects on GSC by impairing the GSC-initiating spherogenesis and inhibits the proliferation of CD133+ cells, while having a low or null effect on differentiated glioblastoma cells and normal human stem cells. Metformin and ATO induce autophagy and apoptosis in glioma cells by inhibiting and stimulating the PI3K/Akt and the mitogen-activated protein kinase pathways, respectively. Both drugs promote differentiation of GSC into non-tumorigenic cells. In this regard, metformin acts via activation of the AMPK-FOXO3 axis, whereas ATO blocks the interleukin 6-induced promotion of STAT3 phosphorylation. Blood-brain barrier, easily crossed by metformin but not by ATO, undergoes important glioblastoma-induced alterations that increase its permeability, thus allowing ATO to distribute more into the glioblastoma bulk than in the normal brain parenchyma. A prompt clinical assessment of metformin and ATO in glioblastoma patients would represent a valid attempt to improve their survival.
Assuntos
Antineoplásicos/farmacologia , Arsenicais/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Metformina/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Óxidos/farmacologia , Quinases Proteína-Quinases Ativadas por AMP , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Animais , Trióxido de Arsênio , Neoplasias Encefálicas/patologia , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/patologia , Humanos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Tolerância a RadiaçãoRESUMO
PURPOSE: The aim of this study was to analyze the characteristics of patients with rectal cancer operated with a microscopic positive margin (R1) and thus avoid these situations or adapt treatment in these particular cases. METHODS: We reviewed all the pathology data of resected specimens from patients with rectal or recto-sigmoid cancer operated with curative intent at the Institute of Oncology "Prof. Dr. Ion Chiricuta" between 2000-2011 (763 patients in 12 years) and the pathology files of patients from other institutions referred for adjuvant treatment to our hospital (318 patients). We included patients with anterior resection, Hartmann's procedure and abdomino-perineal resection, but we excluded patients with local excision and patients with R2/R1 at first, but R0 after re-resection (56 patients). We have identified 31 patients with R1, but had to exclude one case from analysis because this patient was lost to follow-up. RESULTS: With surgery alone the local relapse (LR) was unavoidable. In the neoadjuvant chemoradiation (CRT) group 85.7% of the patients did not develop LR despite of R1. In the adjuvant CRT cohort 50% of the patients were LR-free at 2 years after conventional radiotherapy (p<0.01). CONCLUSION: Based on these results it is concluded that a clear resection margin is extremely important for the local control of rectal cancer, because it cannot be always compensated by adjuvant CRT. In R1 cases neoadjuvant CRT seems to offer better prognosis than adjuvant CRT. To avoid R1 and its consequences a good quality control of total mesorectal excision (TME) is needed and CRT should be done before and not after surgery. R1 after primary surgery needs to be compensated by re-resection if possible, otherwise probably high dose radiotherapy with chemotherapy is needed.
Assuntos
Adenocarcinoma/cirurgia , Neoplasias Retais/cirurgia , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Quimiorradioterapia Adjuvante , Distribuição de Qui-Quadrado , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Neoplasia Residual , Radioterapia Adjuvante , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Estudos Retrospectivos , Fatores de Risco , Romênia , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Colorectal cancer is the fourth most common cancer in men and the third most common cancer in women worldwide. The partial failure of classic therapeutic options makes scientists to doubt the efficacy of systemic treatments in targeting the essential cell populations and achieving cure as a final goal. Overgrowing data suggest that cancer is a disease closely linked to stem cells (SCs). It is well known that the first identification of cancer stem-like cells in acute myeloid leukaemia was soon followed by similar results in solid malignancies, including colorectal cancer, and the classic model for colon carcinogenesis supports the development of sudden mutations that will lead to the activation or inactivation of certain oncogenes or tumor suppressors. Thus, this process may go on for years before the first symptoms and the only cells able to withstand for many years, avoid apoptosis and have a high regenerative capacity are the progenitor cells found at the lower part of colon crypts. A more profound study of the mechanisms and molecular signalling pathways that control the basic characteristics of SCs, such as asymmetrical division or self-renewal, may help comprehend the basic mechanisms of cancer genesis and progression. This will result in the development of new therapeutic agents that may target chemoresistant cell populations and improve the therapeutic results. In the current review we point out the importance of cancer stem-like cells in colorectal oncology from a pathologist's point of view, stating the obvious correlation between histology, embryology and surgical pathology.
Assuntos
Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Células-Tronco Neoplásicas/patologia , Feminino , Humanos , MasculinoRESUMO
High grade gliomas, the most frequent and most malignant brain cancers, grow rapidly and infiltrate the cerebrospinal axis causing deficits in cognition, mobility, balance or speech and are typically resistant to radiation and chemotherapy. Despite recent progress, WHO grade III and IV gliomas still represent a great challenge in oncology, with overall poor outcomes and inevitable lethality. While radiotherapy and temozolomide are considered the standard first-line approach for therapy of newly diagnosed malignant gliomas, the treatment protocols for recurrent tumors remain ill-defined. Increasing evidence suggests that tumors of the central nervous system are derived from proliferatively active neural stem cells residing in defined neuropoietic niches of the adult brain. These cancer stem cells, also identified in other tumors, provide a reservoir of cells with self-renewal capabilities, can maintain the tumor by generating differentiated non-stem tumor cells and are responsible for recurrences after ablative neurosurgical therapy and chemoradiotherapy. The only way to successfully control recurrent malignant gliomas and even hope for a cure in the future is by combining standard chemotherapy with immunotherapy. Despite the apparent improvements of current treatments, it should be realized that the characteristic brain tumor niche may provide recurrent gliomas an "escape mechanism" from anticancer treatments. Thus, the use of targeted molecular therapy drugs may effectively inhibit or at least slow down cancer stem cell proliferation and stop the brain microenvironment from allowing furtive invasion and proliferation of highly aggressive malignant gliomas.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Terapia de Alvo Molecular , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/fisiopatologia , Resistencia a Medicamentos Antineoplásicos , Glioma/diagnóstico , Glioma/epidemiologia , Glioma/fisiopatologia , Humanos , Transdução de SinaisRESUMO
Colorectal cancer (CRC) remains a major health problem worldwide. Angiogenesis is a key process for tumor growth and metastasis. The conversion of tumor cells to an angiogenic phenotype involves the change in the balance of angiogenic growth factors and angiogenesis inhibitors. In our study we evaluated by qRT-PCR the level of expression of 3 growth factors involved in angiogenesis: platelet derived growth factor-B (PDGFb), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) in patients with different stages of colon cancer. Our results showed the level of VEGF increased on all tumor without difference, statistically significant according with tumor stage whereas the others the levels of bFGF and PDGF were higher, statistically significant, on tumor classified stage B compared with stage C. The early implication of these molecules in colon carcinogenesis justifies the development of new biologic individualized therapies.
Assuntos
Neoplasias Colorretais/genética , Fator 2 de Crescimento de Fibroblastos/genética , Proteínas Proto-Oncogênicas c-sis/genética , Fator A de Crescimento do Endotélio Vascular/genética , Neoplasias Colorretais/irrigação sanguínea , Humanos , Neovascularização Patológica , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
One of the main topics of the annual meeting of the American Society for Clinical Oncology in 2011 were the results presented on breast cancer chemotherapy and concomitant administration of the oral antidiabetic metformin. The overall agreement was that current evidence is just enough to dramatically change the clinical practice of oncology, and in our case, brain cancer treatment, and that further research is needed to address the relationship between diabetes, metabolism, insulin analogues and neoplasia. Still, it is very interesting to explore the potentially beneficial effects of metformin in glioma chemo/immunotherapy and wait for results in the clinic. In the current paper we present the cell and molecular aspects of the metabolic syndrome, metformin administration and cancer chemotherapy, with a special emphasis in neuro-oncology, since brain tumors are usually devastating diseases with an extremely high mortality within two years of diagnosis even when surgical, radiotherapeutic and chemotherapeutic interventions are applied.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Síndrome Metabólica/complicações , Metformina/uso terapêutico , Proteínas Quinases Ativadas por AMP/fisiologia , Animais , Transportador de Glucose Tipo 3/fisiologia , Glutationa/metabolismo , Humanos , Espécies Reativas de Oxigênio/metabolismoRESUMO
PURPOSE: Glioblastoma multiforme (GBM) remains one of the most devastating diseases known to man and affects more than 17,000 patients in the United States alone every year. This malignancy infiltrates the brain early in its course and makes complete neurosurgical resection almost impossible. Recent years have brought significant advances in tumor biology, including the discovery that many cancers, including gliomas, appear to be supported by cells with stem-like properties. In the current study we have investigated the effects of combining metformin with the standard treatment-of-care, as this drug, already used in the treatment of diabetes mellitus, has shown surprising results in the treatment of breast cancer, being also associated with lower mortality in several other malignancies. METHODS: The subjects of the current study were 8 patients with newly diagnosed high-grade gliomas, operated at the Department of Neurosurgery - Clinical University Emergency Hospital, Cluj Napoca. Tumor tissue cultures were established and characterized using immunofluorescence microscopy and PCR analysis and the sensitivity to metformin, epidermal growth factor (EGF) and temozolomide (TMZ) was tested. Microvascular density (MVD) assay was performed on the tumor samples. RESULTS: Seven of the 8 cases had a positive correlation between the number of endothelial cells, the phenotype of isolated tumor cells and the response to adjuvant chemoradiotherapy. The isolated tumor cells had a stem-like behavior, being resistant to conventional drugs. In most cases there was no statistical significant difference between TMZ alone and TMZ plus EGF arms, but there was a important difference between TMZ alone and TMZ plus metformin arms in 6 of the cases. CONCLUSION: New drugs and targeted molecular therapies are important for future therapeutics, but sometimes we must not exclude drugs already used in the clinic that might have remarkable results. Such is the case of metformin, a drug used for decades in the treatment of type 2 diabetes mellitus that has proven to enhance the effect of TMZ in the treatment of breast cancer and, starting with this paper, of brain cancer.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Dacarbazina/análogos & derivados , Glioma/tratamento farmacológico , Glioma/patologia , Metformina/uso terapêutico , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Western Blotting , Proliferação de Células/efeitos dos fármacos , Quimioterapia Adjuvante , Dacarbazina/uso terapêutico , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Temozolomida , Resultado do Tratamento , Células Tumorais Cultivadas , Organização Mundial da SaúdeRESUMO
PURPOSE: The purpose of this study was to challenge current knowledge on the potential therapeutic advantages of stem cells in radiotherapy by developing an in vitro model of the healthy tissue surrounding or replacing the widely resected tumor. After radical surgery, the start of radiotherapy is often delayed due to wound healing process, with potential loss of the opportunity for treating microscopic disease instead of macroscopic early recurrence. Hyperfractionated radiotherapy, contrary to the standard one, can extend the limits of radical surgery and shorten the gap before the onset of postoperative radiotherapy, with potential improvement in local control. METHODS: By using both mesenchymal stem cells and pre-differentiated osteoblasts, cultured in proper pro-osteogenic media after cell irradiation, we investigated both the differences in the response to DNA damage between lineages undergoing differentiation in culture and the intensity of the mineralization process. RESULTS: Ionizing radiation stimulated stem cell proliferation and differentiation at 0.5 Gy and 1 Gy, thus confirming in vitro the clinical results of hyperfractionated irradiation randomized trials in head and neck cancers -HNCs-. CONCLUSION: To our knowledge, this study is the first to investigate the biophysics of low dose gamma irradiation on stem cell culture, focusing on the potential applications in radiation oncology. For advanced oral cavity and oropharyngeal cancers, as radical surgery often implies major bone resection, the use of mesenchymal stem cells as bone reconstruction vectors might shorten the onset of adjuvant hyperfractionated radiotherapy which enhances the mineralization process. As postoperative radiotherapy has recently being revisited for osteosarcoma, this scenario could impact also on bone reconstruction process in this pathology.
Assuntos
Fracionamento da Dose de Radiação , Neoplasias de Cabeça e Pescoço/radioterapia , Células-Tronco Mesenquimais/efeitos da radiação , Técnicas de Cultura de Células , Divisão Celular , Separação Celular , Radioisótopos de Cobalto/efeitos adversos , Radioisótopos de Cobalto/uso terapêutico , Relação Dose-Resposta à Radiação , Raios gama , Humanos , Imunofenotipagem , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/imunologia , Osteoblastos/efeitos da radiação , Radioterapia/efeitos adversos , Radioterapia/métodosRESUMO
PURPOSE: glioblastoma multiforme (GBM) still bears a very dismal prognosis even with complete resection followed by adjuvant chemoradiation. The aim of the current study was to evaluate in vitro the antitumor efficacy of arsenic trioxide (ATO) in combination with ionizing radiation plus temozolomide and bevacizumab against cultured glioblastoma stem-like cells, as possible way to increase the therapeutic index in patients diagnosed with recurrent, therapy-refractory GBM. METHODS: stem-like tumor cells isolated from a GBM biopsy were established by cell proliferation assays and upregulation of stem cell markers, as proven by reverse transcription - polymerase chain reaction (RT-PCR). Low concentrations of ATO were added prior to temozolomide, bevacizumab and ionizing irradiation. RESULTS: molecular analysis showed that cells expressed CXCR4, Oct-3/4 and GAPDH when compared to placental mesenchymal stem cells, as well as nestin, GFAP and neurofilament protein. Low concentrations of ATO led to morphologic differentiation, with fewer stem cells in Go state and differentiation-associated cytochemical features, like increased sensitivity to cytostatic drugs and radiotherapy. CONCLUSION: ATO exposure before conventional postoperative chemoradiotherapy for GBM might increase treatment efficacy. Further in vivo experiments on laboratory animals and analysis of absorption rate and side effects are required.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos da radiação , Radiossensibilizantes/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Trióxido de Arsênio , Arsenicais/administração & dosagem , Bevacizumab , Western Blotting , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Células Cultivadas , Terapia Combinada , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Feminino , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Glioblastoma/patologia , Humanos , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos da radiação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Nestina , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Óxidos/administração & dosagem , Placenta/citologia , Placenta/efeitos dos fármacos , Placenta/efeitos da radiação , Gravidez , RNA Mensageiro/genética , Tolerância a Radiação/efeitos dos fármacos , Radiação Ionizante , Receptores CXCR4 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , TemozolomidaRESUMO
PURPOSE: The aim of this study was to investigate the efficiency of the FOLFOX-4 regimen and to evaluate the pharmacokinetics of oxaliplatin in untreated patients with metastatic colorectal cancer. METHODS: 43 patients were enrolled in the study. Patients received oxaliplatin 85 mg/m(2) as 2-h i.v. infusion, on day 1, and bolus 5-fluorouracil (5FU) 400 mg/m(2) plus leucovorin (LV) 200 mg/m(2) followed by 5FU 600 mg/m(2) as 22-h infusion on day 1 and 2, every 2 weeks. The pharmacokinetics of oxaliplatin evaluated in 4 patients was performed in blood, plasma and ultrafiltered plasma (UFT) by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). RESULTS: The overall response rate and the median time to progression (TTP) were 53.49% and 7.1 months, respectively. Grade 3-4 toxic effects were observed in 11 (25.5%) patients. Grade 3 neuropathy was observed in 13.95% of the cases. In univariate analysis only Eastern Cooperative Oncology Group (ECOG) performance status (PS) was correlated with response. No correlation was found between grade 3-4 adverse events and the patient characteristics. The area under the time-concentration curve (AUC) in UFT was 4.8 + or - 0.72 standard deviation (SD) microg h/ml and the total clearance 30.17 + or - 7.75 l/min. The values for volume of distribution and the maximum concentration were 567 + or - 20 liters and 0.38 + or - 0.17 ug/ml, respectively. CONCLUSION: FOLFOX-4 was an effective regimen with good tolerability in previously untreated metastatic colorectal cancer patients. The pharmacokinetics of oxaliplatin was triphasic with a short initial distribution phase and a long terminal elimination phase.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Compostos Organoplatínicos/uso terapêutico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Área Sob a Curva , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Fluoruracila/uso terapêutico , Humanos , Leucovorina/administração & dosagem , Leucovorina/farmacocinética , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/farmacocinética , Oxaliplatina , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE: Brain tumors are the leading cause of cancer mortality in children and remain incurable despite advances in surgery and adjuvant therapies. The failure of malignant gliomas to respond to conventional treatment reflects the unique biology of these tumors, linked to a small population of stem-like precursors. This study describes the characteristics of stem cells isolated from glioblastoma multiforme (GM) and gives insight into the mechanism of brain tumorigenesis. METHODS: Tumor stem-like precursors were identified from primary human GM-derived cell culture using immunocytochemistry and reverse transcription polymerase chain reaction (RT-PCR). Cells were cultured in vitro in stem cell medium supplemented with growth factors and then the capacity of the surviving stem-like precursors to form tumor spheres and to continue to proliferate after chemoradiotherapy were tested. RESULTS: The tumor cells expressed the cellular markers CD133, CD105, CD90, Nanog, Oct 3/4, CXCR4, nestin, glial fibrillary acidic protein (GFAP), neurofilament protein (NF) and human glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Cells also displayed a high proliferative potential despite chemotherapy and irradiation and also had the ability to form spheroids in suspension. CONCLUSION: High grade gliomas contain stem-like precursors, which exhibit neural stem cell properties with tumorigenicity, establishing a novel developmental paradigm in the study of brain carcinogenesis and providing a powerful tool to develop patient-tailored therapy for this devastating disease.
Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Células-Tronco Neoplásicas/fisiologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Feminino , Proteína Glial Fibrilar Ácida/análise , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/química , Fator 3 de Transcrição de Octâmero/análiseRESUMO
BACKGROUND AND PURPOSE: Ovarian cancers are composed of heterogeneous cell populations, including highly proliferative immature precursors and differentiated cells that may belong to different lineages. The main reason why epithelial ovarian cancer is difficult to treat is the unusual mechanism of dissemination that involves local invasion of pelvic and abdominal organs. But, unlike many other carcinomas, initial dissemination rarely requires blood or lymph vessels. Because it has been proven that aggregates of malignant cells within the ascites of patients diagnosed with ovarian cancer represent an impediment to cure such cancers, in the present study we adopted suspension culture combined with anti-cancer regimens as a laboratory strategy for research of the initial process of peritoneal micrometastasis. EXPERIMENTAL DESIGN: MLS human ovarian cancer cells were cultured in serum-free medium. Cells of passage eight were treated in combination with the anticancer agent doxorubicin at different peak plasma concentrations for 24 hours, and then maintained under suspension culture. The acquired increased aggressiveness properties was confirmed by multidrug resistance assays and by their ability to grow in an anchorage-independent manner in vitro as tumor spheroids. RESULTS: Cells selected after chemotherapy had a increased proliferative potential, eliminated Rhodamine 123 in culture and also formed spheroids in suspension. CONCLUSIONS: Here we present direct evidence that the metastasis of human ovarian cancer may be a result of transformation and dysfunction of immature precursor cells in the ovary. Also, spheroid formation may represent a key component of chemotherapy recurrence and a better understanding of these 3D structures can contribute to the development of new treatments for metastatic carcinoma.
Assuntos
Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/secundário , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Epitélio , Feminino , Humanos , Metástase Neoplásica , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/metabolismo , Esferoides Celulares , Células Tumorais CultivadasRESUMO
p53 gene, discovered almost 35 years ago, keeps the main role in cell cycle control, apoptosis pathways and transcription. p53 gene is found mutated in more than 50% of all human cancers in different locations. Many structures from viral to non viral were designed to incorporate and deliver in appropriate conditions forms of p53 gene or its transcripts, systemically to target tumor cells and to eliminate them through apoptosis or to restore the normal tumor suppressor gene role. Each delivery system presents advantages and low performance in relation to immune system recognition and acceptance. One of the major discoveries in the last years, silencing of RNA, represents a powerful tool for inhibiting post transcriptional control of gene expression. According to several studies, the RNA silencing technology for p53 transcripts together with other carriers or transporters at nano level can be used for creating new therapeutic models. RNA interference for p53 uses different double-stranded (ds) molecules like short interfering (si) RNA and, despite the difficulty of introducing them into mammalian cells due to immune system response, it can be exploited in cancer therapy.
Assuntos
Genes Supressores de Tumor/fisiologia , Genes p53 , Terapia Genética/métodos , Neoplasias/terapia , Interferência de RNA/fisiologia , Animais , Apoptose , Ciclo Celular/genética , Divisão Celular/genética , Humanos , Modelos Genéticos , Neoplasias/genética , Neoplasias/patologia , Transcrição GênicaRESUMO
PURPOSE: To evaluate the efficacy of capecitabine (Xeloda) as rescue treatment (2nd, 3rd and 4th line) in patients with relapsed nasopharyngeal carcinoma (NPC) in a phase II study. PATIENTS AND METHODS: Between 5/2002-11/2005, 23 relapsed NPC patients (17 locoregional relapse, 3 metastatic, 3 locoregional + metastatic) received capecitabine 2500 mg/m(2)/d, days 1-14 every 3 weeks, until progression or for a maximum of 6 cycles. PATIENT CHARACTERISTICS: 23 patients (14 men, 9 women) with median age 46 years (range 15-59); ECOG performance status 1 n=21, 2 n=2; histology: undifferentiated carcinoma (WHO type III) n=21, non-keratinizing epidermoid carcinoma (WHO type II), n=2. Capecitabine was given as 2nd--(13 patients), 3rd--(7 patients), and 4th--(3 patients) line chemotherapy. Previous chemotherapy regimes were epirubicin + cisplatin, paclitaxel + carboplatin, paclitaxel + 5-fluorouracil and leucovorin (5-FU/LV) or methotrexate. 104 cycles were given (median 5, range 2-6). Two (9%) patients achieved complete response (CR); 9 (39%) partial response (PR); 9 (39%) stable disease (SD) and 3 (13%) progressed (PD). Toxicity was mild without toxic deaths or grade 4 toxicities. The most frequent toxicities (grades 1-3) were anemia (38%), hand-foot syndrome (23%), leukopenia (13%) and diarrhea (7%). Median follow-up was 10 months (range 2-44). Median overall survival was not reached at 18 months and actuarial one-year survival was 62% (95% confidence interval/CI: 41-80). Median progression-free survival was 14 months. CONCLUSION: Capecitabine is active in relapsed NPC patients, achieving 48% objective responses, with mild toxicity. It is an attractive therapy to be administered in an outpatient setting.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias Nasofaríngeas/tratamento farmacológico , Adolescente , Adulto , Capecitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/análogos & derivados , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/mortalidade , Recidiva Local de Neoplasia/tratamento farmacológico , Cooperação do Paciente , Terapia de SalvaçãoRESUMO
From an oncological perspective, the second most common malignancies in children are brain tumors. Despite the recent therapeutic breakthroughs in this field, concerning surgery, radiotherapy and chemotherapy alike, some cases still have poor outcomes in curability. This is especially the case in patients with high-risk histological types of tumors, and those suffering from residual, remitting and disseminated diseases. Due to the unique neuroanatomical emplacement of brain tumors and their aggressive infiltrative behavior, their total removal remains a demanding task. This can be perceived in the high rates of failure treatment and disease recurrence. Furthermore, the adjacent healthy brain tissue is inevitably damaged in the surgical process of effectively removing these tumors. Thus, stem cell transplantation may be a viable solution for the clinical management of these malignancies, as proven by various recent breakthroughs. In the current concise review, we present the role of next generation sequencing in HLA typing for stem cell transplantation in primary CNS pediatric malignancies.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirurgia , Genótipo , Teste de Histocompatibilidade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/cirurgia , Transplante de Células-Tronco , Alelos , Neoplasias Encefálicas/patologia , Criança , Medicina Baseada em Evidências , Teste de Histocompatibilidade/métodos , Humanos , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Transplante de Células-Tronco/métodos , Resultado do TratamentoRESUMO
AIMS: In patients radically treated for differentiated thyroid carcinoma, we assessed the response of highly-sensitive C-reactive protein, an inflammatory biomarker for cardiovascular risk, after thyroid hormone withholding ("deprivation"), as well as factors potentially influencing this response. MATERIAL AND METHODS: We included 52 adults (mean age 45.6±14.0 years, 35 females) who were disease-free after total thyroidectomy, radioiodine ablation and chronic thyroid hormone therapy. They were lifelong non-smokers without apparent inflammatory comorbidity, cardiovascular history beyond pharmacotherapy-controlled hypertension, anti-dyslipidemic medication, or C-reactive protein >10 mg/L in any study measurement. The index deprivation lasted ≥2 weeks, elevating serum thyrotropin >40 mIU/L or ≥100 × the individual's suppressed level. We examined the relationship of age, number of prior deprivations, and gender with the magnitude of post-deprivation C-reactive protein concentration through multivariable statistical analyses using the F test on linear regression models. RESULTS: Post-deprivation, C-reactive protein reached intermediate cardiovascular risk levels (based on general population studies involving chronic elevation), 1-3 mg/L, in 44.2% of patients and high-risk levels, >3 mg/L, in another 17.3%. Mean C-reactive protein was 1.77±1.50 mg/L, differing significantly in females (2.12±1.66 mg/L) vs. males (1.05±0.69 mg/L, P <0.001). In multivariable analysis, patients ≤45 years old (odds ratio, 95% confidence interval 0.164 [0.049-0.548]) were less likely, and females, more likely (3.571 [1.062-12.009]) to have post-deprivation C-reactive protein ≥1 mg/L. CONCLUSIONS: Thyroid hormone withdrawal frequently elevated C-reactive protein to levels that when present chronically, were associated with increased cardiovascular risk in general population studies.
Assuntos
Proteína C-Reativa/análise , Carcinoma/sangue , Doenças Cardiovasculares/epidemiologia , Neoplasias da Glândula Tireoide/sangue , Adulto , Fatores Etários , Antitireóideos/efeitos adversos , Antitireóideos/uso terapêutico , Biomarcadores/sangue , Carcinoma/imunologia , Carcinoma/patologia , Carcinoma/terapia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/imunologia , Transformação Celular Neoplásica/patologia , Estudos de Coortes , Feminino , Seguimentos , Terapia de Reposição Hormonal , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Risco , Romênia/epidemiologia , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/imunologia , Glândula Tireoide/patologia , Glândula Tireoide/cirurgia , Hormônios Tireóideos/administração & dosagem , Hormônios Tireóideos/uso terapêutico , Neoplasias da Glândula Tireoide/imunologia , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapia , Tireoidectomia/efeitos adversosRESUMO
Parkinson's disease (PD) is a neurodegenerative disease of the central nervous system. Although PD is commonly characterized by well-known clinical manifestations, it also involves imbalances in the cortico-subcortical excitation and inhibition processes. Functional electrical stimulation can improve the motor condition of PD patients as a supplement to levodopa therapy. In this study, clinical (using specific tests) and paraclinical (using single-pulse transcranial magnetic stimulation) examinations revealed an improvement in the motor symptoms and the bilateral activation of the primary motor areas of the upper limbs after unilateral functional electrical stimulation in PD patients.
Assuntos
Potencial Evocado Motor/fisiologia , Córtex Motor/fisiopatologia , Doença de Parkinson/patologia , Doença de Parkinson/terapia , Estimulação Magnética Transcraniana/métodos , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Eletromiografia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
OBJECTIVES: Metformin, the most used oral antidiabetic drug for the treatment of type 2 diabetus mellitus, has proved encouraging results when used in the treatment of various types of cancer such as triple-negative breast cancer. Despite compelling evidence of a role of metformin as an anticancer drug, the mechanisms by which metformin exerts its oncostatic actions are not fully understood yet. Therefore, we tried to bring new insights by analyzing the anti-neoplastic effect of metformin for hepatocellular carcinoma-derived stem-like cells treated with conventional combination chemotherapy. METHODS: Cancer stem-like cells previusly isolated from a hepatocellular carcinoma biopsy were treated with metformin, PIAF chemotherapy regimen and the combination of these two protocols. Measurements of lipid peroxidation, reduced glutathione, fluorescein diacetate and proliferation rates were determined, apart from the autophagy assay and apoptosis determination by chip flow cytometry. RESULTS: Metformin alone and especially metformin in association with PIAF increases oxidative stress within the cells by increasing the levels of lipid peroxids as well as decreasing the levels of reduced glutathione. The MTT cell proliferation assay showed decreased prolife-ration rates for the arm treated with metformin and with the combination of drugs in comparison with the control arm, proving high correlation with the oxidative stress results. The autophagy assay and determination of apoptosis by chip flow cytometry confirmed the results obtained in the previous assays. CONCLUSION: Metformin could be used in chemotherapy treatments to induce reactive oxygen species and increase the cytostatics effects within the tumor cell. Still, further experiments must be carried out on murine models before we can move on and use this drugs in the adjuvant setting for unresectable primary liver cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Metformina/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Doxorrubicina/farmacologia , Fluoruracila/farmacologia , Glutationa/metabolismo , Humanos , Interferon-alfa/farmacologia , Neoplasias Hepáticas/tratamento farmacológicoRESUMO
Although the treatment for colorectal cancer has seen considerable progress during the past few years, the mortality associated with this type of tumor remains high. This article presents the existing methods of treatment, focusing on the new treatments made possible by the advances in the field of normal and tumor stem cells. Starting from the normal architecture of the colon and the properties of the cells identified in it, we sought to present a few notions concerning these cells which have a direct relevance for both pathology and treatment. The manner in which they divide (symmetrically or asymmetrically) as well as the molecules which control their circulation through the body are just a few examples which are likely to influence the treatment of colorectal cancer in the future.
Assuntos
Neoplasias Colorretais/patologia , Células-Tronco , Colo/citologia , Neoplasias Colorretais/terapia , Humanos , Terapia de Alvo Molecular , Metástase Neoplásica , Células-Tronco Neoplásicas , Reto/citologiaRESUMO
Over the past years medicine has undergone intensive changes, evolving from classical semiology and internal medicine to individualized treatments, based on recent breakthroughs in immunology and genetics. This concept has had a profound impact in all medical specialties and as a consequence pharmacology and various treatment plans will be based on monoclonal antibodies and targeted cell therapies. One such target is the SDF-1-CXCR4 axis bacause it plays a critical role in many physiological processes that involve cell migration and cell fate decisions, ranging from stem cell homing, angiogenesis and neuronal development to immune cell trafficking. The chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1alpha are also implicated in various pathological conditions, including metastatic spread and HIV infection. In this review, we present the concept that the SDF-1-CXCR4 axis is a master regulator of trafficking of both normal and cancer stem cells, based on the growing evidence that it plays a pivotal role in the regulation of trafficking of normal hematopoietic stem cells and their homing to the bone marrow. Because most malignancies originate in the progenitor cell compartment, cancer stem cells also express CXCR4 on their surface and migrate to organs that highly express SDF-1. Hence, we postulate that the metastasis of cancer stem cells and trafficking of normal stem cells involve similar mechanisms, which may be regulated by several small molecules related to inflammation. Consequently, strategies aimed at modulating the SDF-1-CXCR4 axis could have important clinical applications in both tissue engineering and in clinical hematology and oncology to inhibit metastasis of cancer stem cells.