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1.
Int J Mol Sci ; 20(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540386

RESUMO

Ultrasmall polyaminocarboxylate-coated gold nanoparticles (NPs), Au@DTDTPA and Au@TADOTAGA, that have been recently developed exhibit a promising potential for image-guided radiotherapy. In order to render the radiosensitizing effect of these gold nanoparticles even more efficient, the study of their localization in cells is required to better understand the relation between the radiosensitizing properties of the agents and their localization in cells and in tumors. To achieve this goal, post-functionalization of Au@DTDTPA nanoparticles by near-infrared (NIF) organic dyes (aminated derivative of cyanine 5, Cy5-NH2) was performed. The immobilization of organic Cy5-NH2 dyes onto the gold nanoparticles confers to these radiosensitizers fluorescence properties which can be exploited for monitoring their internalization in cancerous cells, for determining their localization in cells by fluorescence microscopy (a common and powerful imaging tool in biology), and for following up on their accumulation in tumors after intravenous injection.


Assuntos
Carbocianinas/análise , Corantes Fluorescentes/análise , Ouro/análise , Nanopartículas Metálicas/análise , Neoplasias/diagnóstico por imagem , Radiossensibilizantes/análise , Animais , Carbocianinas/administração & dosagem , Linhagem Celular Tumoral , Feminino , Corantes Fluorescentes/administração & dosagem , Ouro/administração & dosagem , Humanos , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia de Fluorescência/métodos , Imagem Óptica/métodos , Poliaminas/análise , Radiossensibilizantes/administração & dosagem
2.
Adv Drug Deliv Rev ; 138: 344-357, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30414495

RESUMO

Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor. Despite new knowledges on the genetic characteristics, conventional therapy for GBM, tumor resection followed by radiotherapy and chemotherapy using temozolomide is limited in efficacy due to high rate of recurrence. GBM is indeed one of the most complex and difficult cancer to treat mainly due to its highly invasive properties and the standard treatments are thus rarely curative. Major challenges in the treatment of GBM are the limitation of irreversible brain damage, the infiltrative part of the tumor which is the ultimate cause of recurrence, the difficulty of identifying tumor margins and disseminated tumor cells, and the transport across the blood-brain barrier in order to obtain a sufficient therapeutic effect for pharmalogical agents. Considering these limitations, this review explores the in vivo potential of metal-based nanoparticles for hyperthermia, radiotherapy and photodynamic therapy. This article describes and clearly outlines the recent in vivo advances using innovative therapeutic metallic nanoparticles such as iron oxide, silver, gadolinium and gold nanoparticles.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Nanopartículas Metálicas/administração & dosagem , Estimulação Física , Animais , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Humanos , Hipertermia Induzida , Fotoquimioterapia
3.
EJNMMI Res ; 8(1): 51, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29904818

RESUMO

BACKGROUND: Tracers triggering αvß3 integrins, such as certain RGD-containing peptides, were found promising in previous pilot studies characterizing high-grade gliomas. However, only limited comparisons have been performed with current PET tracers. This study aimed at comparing the biodistribution of 18F-fluorodeoxyglucose (18F-FDG) with that of 68Ga-NODAGA-RGD, an easily synthesized monomeric RGD compound with rapid kinetics, in two different rodent models of engrafted human glioblastoma. METHODS: Nude rodents bearing human U87-MG glioblastoma tumor xenografts in the flank (34 tumors in mice) or in the brain (5 tumors in rats) were analyzed. Kinetics of 68Ga-NODAGA-RGD and of 18F-FDG were compared with PET imaging in the same animals, along with additional autohistoradiographic analyses and blocking tests for 68Ga-NODAGA-RGD. RESULTS: Both tracers showed a primary renal route of clearance, although with faster clearance for 68Ga-NODAGA-RGD resulting in higher activities in the kidneys and bladder. The tumor activity from 68Ga-NODAGA-RGD, likely corresponding to true integrin binding (i.e., suppressed by co-injection of a saturating excess of unlabeled RGD), was found relatively high, but only at the 2nd hour following injection, corresponding on average to 53% of total tumor activity. Tumor uptake of 68Ga-NODAGA-RGD decreased progressively with time, contrary to that of 18F-FDG, although 68Ga-NODAGA-RGD exhibited 3.4 and 3.7-fold higher tumor-to-normal brain ratios on average compared to 18F-FDG in mice and rat models, respectively. Finally, ex-vivo analyses revealed that the tumor areas with high 68Ga-NODAGA-RGD uptake also exhibited the highest rates of cell proliferation and αv integrin expression, irrespective of cell density. CONCLUSIONS: 68Ga-NODAGA-RGD has a high potential for PET imaging of glioblastomas, especially for areas with high integrin expression and cell proliferation, although PET recording needs to be delayed until the 2nd hour following injection in order to provide sufficiently high integrin specificity.

4.
Theranostics ; 7(2): 436-451, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28255341

RESUMO

Despite recent progress in conventional therapeutic approaches, the vast majority of glioblastoma recur locally, indicating that a more aggressive local therapy is required. Interstitial photodynamic therapy (iPDT) appears as a very promising and complementary approach to conventional therapies. However, an optimal fractionation scheme for iPDT remains the indispensable requirement. To achieve that major goal, we suggested following iPDT tumor response by a non-invasive imaging monitoring. Nude rats bearing intracranial glioblastoma U87MG xenografts were treated by iPDT, just after intravenous injection of AGuIX® nanoparticles, encapsulating PDT and imaging agents. Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) allowed us an original longitudinal follow-up of post-treatment effects to discriminate early predictive markers. We successfully used conventional MRI, T2 star (T2*), Diffusion Weighted Imaging (DWI) and MRS to extract relevant profiles on tissue cytoarchitectural alterations, local vascular disruption and metabolic information on brain tumor biology, achieving earlier assessment of tumor response. From one day post-iPDT, DWI and MRS allowed us to identify promising markers such as the Apparent Diffusion Coefficient (ADC) values, lipids, choline and myoInositol levels that led us to distinguish iPDT responders from non-responders. All these responses give us warning signs well before the tumor escapes and that the growth would be appreciated.


Assuntos
Monitoramento de Medicamentos/métodos , Glioblastoma/diagnóstico , Glioblastoma/terapia , Imagem por Ressonância Magnética , Espectroscopia de Ressonância Magnética/métodos , Fotoquimioterapia , Prótons , Animais , Meios de Contraste/administração & dosagem , Modelos Animais de Doenças , Xenoenxertos , Estudos Longitudinais , Nanopartículas/administração & dosagem , Fármacos Fotossensibilizantes/administração & dosagem , Ratos Nus , Resultado do Tratamento
5.
Int J Nanomedicine ; 11: 6169-6179, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27920524

RESUMO

This article addresses the in silico-in vitro prediction issue of organometallic nanoparticles (NPs)-based radiosensitization enhancement. The goal was to carry out computational experiments to quickly identify efficient nanostructures and then to preferentially select the most promising ones for the subsequent in vivo studies. To this aim, this interdisciplinary article introduces a new theoretical Monte Carlo computational ranking method and tests it using 3 different organometallic NPs in terms of size and composition. While the ranking predicted in a classical theoretical scenario did not fit the reference results at all, in contrast, we showed for the first time how our accelerated in silico virtual screening method, based on basic in vitro experimental data (which takes into account the NPs cell biodistribution), was able to predict a relevant ranking in accordance with in vitro clonogenic efficiency. This corroborates the pertinence of such a prior ranking method that could speed up the preclinical development of NPs in radiation therapy.


Assuntos
Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Método de Monte Carlo , Nanopartículas/administração & dosagem , Radiossensibilizantes/farmacocinética , Simulação por Computador , Humanos , Técnicas In Vitro , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Nanoestruturas/química , Distribuição Tecidual , Células Tumorais Cultivadas
6.
Life Sci ; 137: 74-80, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26239438

RESUMO

AIMS: Glioma initiating cells (GICs) represent a subpopulation of tumor cells endowed with self-renewal and multilineage differentiation capacity but also with innate resistance to cytotoxic agents, a feature likely to pose major clinical challenges towards the complete eradication of minimal residual disease in glioma patients. MATERIALS AND METHODS: In this work, GICs were obtained from two patient-derived high-grade gliomas xenograft model, expressing differently EGFR. GICs were exposed to anti-EGFR monoclonal antibody cetuximab during 48h in 1% or 21% oxygen tension. Cell viability and self-renewal capacity were then evaluated as well as their angiogenic properties. KEY FINDINGS: GICs were sensitive to cetuximab only in normoxic condition whatever the EGFR status. Nevertheless, under hypoxia cetuximab was able to decrease the self-renewal capacity as well as the expression of CD133 while expression of GFAP increased. Moreover, cetuximab decreased the effect of GICs on endothelial cell migration under hypoxia. SIGNIFICANCE: Consequently, anti-EGFR therapy can be envisaged to target specifically GICs in order to limit the tumor recurrence.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Hipóxia Celular , Cetuximab/farmacologia , Receptores ErbB/antagonistas & inibidores , Glioma/tratamento farmacológico , Glioma/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Moduladores da Angiogênese/farmacologia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Neoplasias Encefálicas/metabolismo , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Receptores ErbB/imunologia , Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Glioma/metabolismo , Humanos , Células Tumorais Cultivadas
7.
Theranostics ; 5(9): 1030-44, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26155318

RESUMO

This review focuses on the radiosensitization strategies that use high-Z nanoparticles. It does not establish an exhaustive list of the works in this field but rather propose constructive criticisms pointing out critical factors that could improve the nano-radiation therapy. Whereas most reviews show the chemists and/or biologists points of view, the present analysis is also seen through the prism of the medical physicist. In particular, we described and evaluated the influence of X-rays energy spectra using a numerical analysis. We observed a lack of standardization in preclinical studies that could partially explain the low number of translation to clinical applications for this innovative therapeutic strategy. Pointing out the critical parameters of high-Z nanoparticles radiosensitization, this review is expected to contribute to a larger preclinical and clinical development.


Assuntos
Nanopartículas/administração & dosagem , Radiossensibilizantes/administração & dosagem , Radioterapia/métodos , Animais , Avaliação Pré-Clínica de Medicamentos , Radiação Eletromagnética , Raios X
8.
J Control Release ; 182: 1-12, 2014 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-24631860

RESUMO

The activity of synthetic interfering nucleic acids (siRNAs) relies on the capacity of delivery systems to efficiently transport nucleic acids into the cytosol of target cells. The pyridylthiourea-grafted 25KDa polyethylenimine (πPEI) is an excellent carrier for siRNA delivery into cells and it was extensively investigated in this report. Quantification of the siRNA-mediated gene silencing efficiency indicated that the πPEI specific delivery activity at the cell level may be measured and appears relatively constant in various cell lines. Delivery experiments assaying inhibitors of various entry pathways or concanamycin A, an inhibitor of the H(+)/ATPase vacuolar pump showed that the πPEI/siRNA polyplexes did not require any specific entry mode but strongly relied on vacuolar acidification for functional siRNA delivery. Next, πPEI polyplexes containing a siRNA targeting the transcription factor HIF-1α, known to be involved in tumor progression, were locally injected into mice xenografted with a human glioblastoma. A 55% reduction of the level of the target mRNA was observed at doses comparable to those used in vitro when the πPEI delivery activity was calculated per cell. Altogether, our study underscores the usefulness of "simple"/rough cationic polymers for siRNA delivery despite their intrinsic limitations. The study underscores as well as that bottom-up strategies make sense. The in vitro experiments can precede in vivo administration and be of high value for selection of the carrier with enhanced specific delivery activity and parallel other research aiming at improving synthetic delivery systems for resilience in the blood and for enhanced tissue-targeting capacity.


Assuntos
Polietilenoimina/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Tioureia/análogos & derivados , Tioureia/administração & dosagem , Animais , Linhagem Celular , Linhagem Celular Tumoral , Cricetinae , Feminino , Inativação Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos , Neoplasias/genética , Neoplasias/terapia , Polietilenoimina/química , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/química , Tioureia/química
9.
PLoS One ; 8(7): e68333, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23874590

RESUMO

In high-grade gliomas, the identification of patients that could benefit from EGFR inhibitors remains a challenge, hindering the use of these agents. Using xenografts models, we evaluated the antitumor effect of the combined treatment "gefitinib + radiotherapy" and aimed to identify the profile of responsive tumors. Expression of phosphorylated proteins involved in the EGFR-dependent signaling pathways was analyzed in 10 glioma models. We focused on three models of anaplastic oligodendrogliomas (TCG2, TCG3 and TCG4) harboring high levels of phospho-EGFR, phospho-AKT and phospho-MEK1. They were treated with gefitinib (GEF 75 mg/kg/day x 5 days/week, for 2 weeks) and/or fractionated radiotherapy (RT: 5x2Gy/week for 2 weeks). Our results showed that GEF and/or RT induced significant tumor growth delays. However, only the TCG3 xenografts were highly responsive to the combination GEF+RT, with ∼50% of tumor cure. Phosphoproteins analysis five days after treatment onset demonstrated in TCG3 xenografts, but not in TCG2 model, that the EGFR-dependent pathways were inhibited after GEF treatment. Moreover, TCG3-bearing mice receiving GEF monotherapy exhibited a transient beneficial therapeutic response, rapidly followed by tumor regrowth, along with a major vascular remodeling. Taken together, our data evoked an "EGFR-addictive" behavior for TCG3 tumors. This study confirms that combination of gefitinib with fractionated irradiation could be a potent therapeutic strategy for anaplastic oligodendrogliomas harboring EGFR abnormalities but this treatment seems mainly beneficial for "EGFR-addictive" tumors. Unfortunately, neither the usual molecular markers (EGFR amplification, PTEN loss) nor the basal overexpression of phosphoproteins were useful to distinguish this responsive tumor. Evaluating the impact of TKIs on the EGFR-dependent pathways during the treatment might be more relevant, and requires further validation.


Assuntos
Quimiorradioterapia/métodos , Receptores ErbB/metabolismo , Oligodendroglioma/tratamento farmacológico , Oligodendroglioma/radioterapia , Quinazolinas/uso terapêutico , Transdução de Sinais/fisiologia , Animais , Terapia Combinada/métodos , Fracionamento da Dose de Radiação , Feminino , Gefitinibe , Humanos , Imunoensaio , Imuno-Histoquímica , Camundongos , Fosfoproteínas/metabolismo , Quinazolinas/farmacologia , Estatísticas não Paramétricas , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
10.
Cancer Res ; 73(16): 5040-52, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23774208

RESUMO

The DNA repair protein damaged DNA-binding 2 (DDB2) has been implicated in promoting cell-cycle progression by regulating gene expression. DDB2 is selectively overexpressed in breast tumor cells that are noninvasive, but not in those that are invasive. We found that its overexpression in invasive human breast tumor cells limited their motility and invasiveness in vitro and blocked their ability to colonize lungs in vivo, defining a new function for DDB2 in malignant progression. DDB2 overexpression attenuated the activity of NF-κB and the expression of its target matrix metalloprotease 9 (MMP9). Mechanistic investigations indicated that DDB2 decreased NF-κB activity by upregulating expression of IκBα by binding the proximal promoter of this gene. This effect was causally linked to invasive capacity. Indeed, knockdown of DDB2-induced IκBα gene expression restored NF-κB activity and MMP9 expression, along with the invasive properties of breast tumor cells overexpressing DDB2. Taken together, our findings enlighten understanding of how breast cancer cells progress to an invasive phenotype and underscore potential clinical interest in DDB2 as a prognostic marker or therapeutic target in this setting.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , NF-kappa B/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Células MCF-7 , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , Invasividade Neoplásica , Prognóstico , Regiões Promotoras Genéticas , Transcrição Genética , Regulação para Cima/genética
11.
PLoS One ; 8(4): e61758, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23626723

RESUMO

Long chain alkylphenols are man-made compounds still present in industrial and agricultural processes. Their main use is domestic and they are widespread in household products, cleansers and cosmetics, leading to a global environmental and human contamination. These molecules are known to exert estrogen-like activities through binding to classical estrogen receptors. In vitro, they can also interact with the G-protein coupled estrogen receptor. Testicular germ cell tumor etiology and progression are proposed to be stimulated by lifelong estrogeno-mimetic exposure. We studied the transduction signaling pathways through which an alkyphenol mixture triggers testicular cancer cell proliferation in vitro and in vivo. Proliferation assays were monitored after exposure to a realistic mixture of 4-tert-octylphenol and 4-nonylphenol of either TCam-2 seminoma derived cells, NT2/D1 embryonal carcinoma cells or testis tumor in xenografted nude mice. Specific pharmacological inhibitors and gene-silencing strategies were used in TCam-2 cells in order to demonstrate that the alkylphenol mix triggers CREB-phosphorylation through a rapid, ERα36-PI3kinase non genomic pathway. Microarray analysis of the mixture target genes revealed that this pathway can modulate the expression of the DNA-methyltransferase-3 (Dnmt3) gene family which is involved in DNA methylation control. Our results highlight a key role for ERα36 in alkylphenol non genomic signaling in testicular germ cell tumors. Hence, ERα36-dependent control of the epigenetic status opens the way for the understanding of the link between endocrine disruptor exposure and the burden of hormone sensitive cancers.


Assuntos
Carcinógenos Ambientais/farmacologia , Carcinoma/genética , Receptor alfa de Estrogênio/genética , Fenóis/farmacologia , Seminoma/genética , Neoplasias Testiculares/genética , Androstadienos/farmacologia , Animais , Carcinoma/metabolismo , Carcinoma/patologia , Proliferação de Células/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Epigênese Genética/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Seminoma/metabolismo , Seminoma/patologia , Transdução de Sinais , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia , Wortmanina
12.
Cancer Res ; 72(14): 3463-70, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22593187

RESUMO

Integrins play a role in the resistance of advanced cancers to radiotherapy and chemotherapy. In this study, we show that high expression of the α5 integrin subunit compromises temozolomide-induced tumor suppressor p53 activity in human glioblastoma cells. We found that depletion of the α5 integrin subunit increased p53 activity and temozolomide sensitivity. However, when cells were treated with the p53 activator nutlin-3a, the protective effect of α5 integrin on p53 activation and cell survival was lost. In a functional p53 background, nutlin-3a downregulated the α5 integrin subunit, thereby increasing the cytotoxic effect of temozolomide. Clinically, α5ß1 integrin expression was associated with a more aggressive phenotype in brain tumors, and high α5 integrin gene expression was associated with decreased survival of patients with high-grade glioma. Taken together, our findings indicate that negative cross-talk between α5ß1 integrin and p53 supports glioma resistance to temozolomide, providing preclinical proof-of-concept that α5ß1 integrin represents a therapeutic target for high-grade brain tumors. Direct activation of p53 may remain a therapeutic option in the subset of patients with high-grade gliomas that express both functional p53 and a high level of α5ß1 integrin.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Dacarbazina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Integrina alfa5beta1/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular Tumoral , Dacarbazina/uso terapêutico , Humanos , Imidazóis/farmacologia , Integrina alfa5beta1/metabolismo , Camundongos , Piperazinas/farmacologia , Temozolomida , Resultado do Tratamento
13.
J Radiat Res ; 53(1): 101-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22302050

RESUMO

Radiotherapy is an integral part of overall cancer therapy. One of the most serious adverse effects of irradiation concern, for long-term survivors, the development of post-radiation sarcoma (PRS) in healthy tissues located within the irradiated area. PRS have bad prognosis and are often detected at a late stage. Therefore, it is obvious that the early detection PRS is a key-point and the development of preclinical models is worthy to evaluate innovative diagnostic and therapeutic procedures. The aim of this study was to develop a spontaneous rodent model of PRS and to evaluate the potency of Positron Emission Tomography (PET) for early detection. Fifteen Wistars rats were irradiated unilateraly on the hindlimb with a single dose of 30 Gy. Sequential analysis was based on observational staging recordings, Computerized Tomography (CT) scanning and PET. Tumors were removed and, histopathological and immunochemistry analyses were performed. Among the irradiated rats, 12 sarcomas (80%) were detected. All tumors occurred naturallty within the irradiated hindlimb and were highly aggressive since most tumors (75%) were successfully transplanted and maintained by serial transplantation into nude mice. Upon serial staging recordings, using PET, was found to enable the detection of PRS earlier after irradiation than with the other methods (i.e. 11.9 ± 1.8 vs 12.9 ± 2.6 months). These results confirmed the interest of experimental models of PRS for the preclinical evaluation of innovative diagnostic strategies and confirmed the potency of PET for early detection of PRS. This preclinical model of PRS can also be proposed for the evaluation of therapeutic strategies.


Assuntos
Modelos Animais , Neoplasias Induzidas por Radiação/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Sarcoma Experimental/diagnóstico por imagem , Neoplasias de Tecidos Moles/diagnóstico por imagem , Animais , Biomarcadores Tumorais/análise , Radioisótopos de Cobalto , Diagnóstico Precoce , Radioisótopos de Flúor , Fluordesoxiglucose F18 , Membro Posterior , Masculino , Camundongos , Camundongos Nus , Invasividade Neoplásica , Transplante de Neoplasias , Neoplasias Induzidas por Radiação/patologia , Compostos Radiofarmacêuticos , Ratos , Ratos Wistar , Sarcoma Experimental/etiologia , Sarcoma Experimental/patologia , Neoplasias de Tecidos Moles/etiologia , Neoplasias de Tecidos Moles/patologia , Tomografia Computadorizada por Raios X
14.
Int J Cancer ; 131(3): 601-11, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21901744

RESUMO

Caveolin-1 plays a crucial role in the development of cancer and its progression. We previously reported that glioblastoma cells expressing low levels of caveolin-1 exerted a more aggressive phenotype than cells expressing high levels. Such phenotype was due to the induction of α(5) ß(1) integrin subsequent to the depletion of caveolin-1. Caveolin-1 was identified as a transcriptional repressor of α(5) ß(1) integrin. The current study was designed to identify in vitro, the molecular mechanisms by which caveolin-1 controls α(5) ß(1) integrin expression and to determine if a negative correlation between caveolin-1 and α(5) ß(1) integrins also exists in biopsies and xenografted human brain tumors. We showed that depletion of caveolin-1 lead to the activation of the TGFß/TGFßRI/Smad2 pathway which in turn induced the expression of α(5) ß(1) integrins. We showed that cells expressing the lowest levels of caveolin-1 but the highest levels of α(5) ß(1) integrins and TGFßRI were the most sensitive to a α(5) ß(1) integrin antagonist and a TGFßRI inhibitor. Screening human glioma biopsies and human glioblastoma xenografts, we isolated subgroups with either low levels of caveolin-1 but high levels of α(5) ß(1) integrin and TGFßRI or high levels of caveolin-1 but low levels of α(5) ß(1) integrin and TGFßRI. In conclusion, caveolin-1 controls α(5) ß(1) integrin expression through the TGFß/TGFßRI/Smad2 pathway. The status of caveolin-1/α(5) ß(1) integrins/TGFßRI might be a useful marker of the tumor evolution/prognosis as well as a predictor of anti-TGFß or anti-α(5) ß(1) integrin therapies.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Caveolina 1/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patologia , Integrina alfa5beta1/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Humanos , Integrina alfa5beta1/antagonistas & inibidores , Integrina alfa5beta1/biossíntese , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Nus , Transplante de Neoplasias , Interferência de RNA , RNA Interferente Pequeno , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/biossíntese , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Proteína Smad2/metabolismo , Transcrição Genética , Transplante Heterólogo
15.
Int J Radiat Oncol Biol Phys ; 79(3): 892-900, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21168283

RESUMO

PURPOSE: To investigate the influence of the bortezomib (BTZ) on malignant glioma radiosensitivity in two xenograft models. METHODS AND MATERIALS: For TCG3 and U87 models, we evaluated the antitumor activity of BTZ, radiotherapy, and BTZ plus radiothearapy according to two therapeutic schedules: a "nonfractionated" schedule corresponding to a single dose of treatment per week, and a "fractionated" schedule corresponding to the same weekly dose divided into 5 fractions. Treatments influence on proliferation and apoptosis indexes, cell cycle distribution, and nuclear factor-κB pathway were explored. RESULTS: The radiosensitizing properties of BTZ observed with the nonfractionated schedule were lost with the fractionated schedule. Bortezomib-mediated radiosensitization was associated with an increased apoptosis response and major changes in cell proliferation, but the nuclear factor-κB pathway was not involved. Most of the cellular effects induced by BTZ when tumors received a single irradiation were cancelled out if radiotherapy was fractionated. CONCLUSION: The influence of BTZ on glioma radiosensitivity seems to depend on the treatment fractionation schedule, emphasizing the need to clarify the mechanisms underlying BTZ's radiosensitizing effects before further clinical trials are initiated.


Assuntos
Ácidos Borônicos/farmacologia , Glioma/radioterapia , Pirazinas/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Animais , Apoptose/efeitos dos fármacos , Bortezomib , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Terapia Combinada/métodos , Fracionamento da Dose de Radiação , Esquema de Medicação , Feminino , Glioma/metabolismo , Glioma/patologia , Camundongos , Camundongos Nus , NF-kappa B/metabolismo , Distribuição Aleatória , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Int J Oncol ; 37(6): 1555-63, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21042725

RESUMO

The implication of loss of PTEN expression in resistance to targeted therapy has already been described in many tumor types. The absence of response to anti-EGFR agents in PTEN-deficient tumors relies on persistent activation of signaling pathways downstream of pEGFR. To investigate the role of PTEN loss of expression in head and neck squamous cell carcinoma (HNSCC) response to cetuximab, we used siRNA in Cal 27 cells and then evaluated key signaling protein activation (pAKT and pERK 1/2) as well as cell viability and proliferation. PTEN silencing in Cal 27 cells led to a constitutive activation of signaling pathways evidenced by a strong increase in pAKT and pERK 1/2 expression. Moreover, PTEN-silenced cells did not show any significant changes either in cell viability or proliferation, only slight modifications on cell cycle. Additionally and unpredictably, our results indicated that PTEN silencing, led to a drastic reduction in pEGFR expression whereas total EGFR level did not significantly vary. Strikingly, despite this overactivation of signaling pathways ruling cell survival and proliferation in siPTEN cells, cetuximab fully exerted pAKT and pERK 1/2 inhibition of expression, similarly to its effect in untransfected Cal 27 cells. In conclusion, our study established that in Cal 27 cells, cetuximab keeps full ability to inhibit EGFR-dependent mechanisms, as shown by a decreased pAKT and pERK 1/2 level of expression, despite a strong PTEN silencing-induced overactivation. In Cal 27 cells, loss of PTEN expression does not lead to a loss of cetuximab efficacy in inhibiting EGFR-downstream signaling pathways, contrarily to data shown in previous works conducted in other tumor types.


Assuntos
Anticorpos Monoclonais/uso terapêutico , PTEN Fosfo-Hidrolase/genética , Interferência de RNA , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Antinematódeos/farmacologia , Antinematódeos/uso terapêutico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patologia , Carcinoma/terapia , Carcinoma de Células Escamosas , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Cetuximab , Terapia Combinada , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Terapia Genética/métodos , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Imunoterapia/métodos , Neoplasias de Células Escamosas/genética , Neoplasias de Células Escamosas/metabolismo , Neoplasias de Células Escamosas/patologia , Neoplasias de Células Escamosas/terapia , PTEN Fosfo-Hidrolase/antagonistas & inibidores , Interferência de RNA/fisiologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Resultado do Tratamento
17.
Oncol Rep ; 20(5): 1283-7, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18949434

RESUMO

Bortezomib and other proteasome inhibitors have demonstrated an interesting antitumor activity against glioma cell lines. The present study aimed to evaluate the cytotoxic potential of bortezomib in vivo on two human malignant glioma xenografts using doses relevant to clinical practice. The TCG3 and U87 malignant glioma xenografts were heterotopically implanted onto nude mice. Bortezomib effects were evaluated using the three different doses of 0.25, 0.45 and 0.90 mg/kg. Proteasome chymotrypsin-like activity was measured by a fluorimetric method. Analysis of the cell cycle distribution was performed after propidium iodide staining. The apoptotic rate and proliferative index were determined by an immunohistochemical detection of cleaved caspase-3 and Ki-67, respectively. Our data showed that bortezomib induced a dose-dependent inhibition of proteasome chymotrypsin-like activity in the two glioma models. Maximal inhibition was achieved 24 h after drug injection and was approximately 30% of basal proteasome activity. However, this effect did not induce any increase in the apoptotic rate and did not modify cell cycle distribution. At the maximal dose tested (0.90 mg/kg), bortezomib did not show any growth delay as compared to untreated tumors, in either of the xenograft models. In conclusion, our study is the first to demonstrate that bortezomib, at a clinically relevant dose, did not have any effect on the apoptosis and proliferation of malignant gliomas in vivo. These results contrast with the promising preclinical data obtained in vitro with this drug and emphasize the importance of performing preclinical studies on animal models, in conditions close to clinical settings.


Assuntos
Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Glioma/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Pirazinas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Bortezomib , Feminino , Humanos , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Anticancer Drugs ; 19(10): 991-8, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18827564

RESUMO

Malignant glioma patients have a life expectancy reduced to about 15 months despite aggressive surgery, radiotherapy (RT), and chemotherapy. Doxorubicin has shown a marked cytotoxic effect against malignant glioma cells in vitro. The brain exposure to this drug is, however, hindered by the blood-brain barrier. Encapsulation of doxorubicin in liposomal carriers has been shown to reduce toxicities and to improve brain tumors exposure to doxorubicin. In this study, we evaluated the radiosensitizing properties of a nonpegylated liposomal doxorubicin (Myocet, MYO) on two subcutaneous (U87 and TCG4) and one intracranial (U87) malignant glioma models xenografted on nude mice. Doxorubicin biodistribution was assessed by a high-performance liquid chromatography method. Antitumor efficacy was investigated by tumor volume measurements and mice survival determination. We showed that (i) encapsulation of doxorubicin ensured a preferential deposition of doxorubicin in tumoral tissue in comparison with free doxorubicin; (ii) doxorubicin accumulated in both subcutaneous and intracranial tumors during repeated injections of MYO and this accumulation was linked to the potentiation of RT efficacy on two subcutaneous models; (iii) MYO was unable to improve the antitumoral efficacy of RT on an intracranial glioma model. Finally, this study emphasizes the importance of performing preclinical studies on models closer as possible of human tumors and localization to be more predictive of therapeutic effects observed in humans.


Assuntos
Doxorrubicina/uso terapêutico , Glioma/radioterapia , Radiossensibilizantes/uso terapêutico , Animais , Neoplasias Encefálicas/radioterapia , Feminino , Glioma/patologia , Humanos , Camundongos , Neoplasias Cutâneas/radioterapia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Int J Oncol ; 32(1): 69-77, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18097544

RESUMO

Relationship between haemoglobin levels and tumour oxygenation has been already reported. The purpose of this work was to compare in human malignant glioma-bearing mice the sensitivity of two well established techniques of tumour hypoxia assessment, especially their ability to detect expected weak variations of tumour oxygenation status associated to haemoglobin level modifications. The relationship between tumour hypoxia and glucose metabolism was also investigated. Experiments were performed on a human malignant glioma (GBM Nan1) xenografted into nude mice. Twenty-four hours after tumour implantation, animals were randomized into three groups: 'Anaemia' for mice subjected to repeated blood samplings, 'Control', and 'rHuEPO' for mice receiving recombinant human erythropoietin. Once the tumours reached a volume of 300+/-100 mm(3), tumour hypoxia was assessed both using the pO(2)-Histograph, Eppendorftrade mark and the pimonidazole binding assay. Glucose metabolism was evaluated by (18)F-FDG autoradiography and compared with the pimonidazole binding distribution pattern. Repeated blood samplings significantly reduced mean haemoglobin levels (10.9+/-2.0 g/dl), inducing chronic anaemia in mice, while daily administration of rHuEPO led to increase of haemoglobin levels (15.8+/-2.0 g/dl). Oxygenation status evaluated by a microelectrode was worsened in anaemic mice (mean pO(2) in tumour = 6.9+/-0.8 mmHg) and improved in rHuEPO-treated animals (mean pO(2)in tumour = 11.4+/-1.2 mmHg). No correlation was observed between the oxygen-sensitive probe and pimonidazole labelling results: both techniques give different but complementary information about tumour hypoxia. Areas of high pimonidazole binding and areas of high (18)F-FDG uptake superimposed well. Present results confirm that modification of haemoglobin levels leads to alteration of tumour oxygenation status. These variations were detectable using the oxygen-sensitive electrode but not the pimonidazole binding assay. The strong correlation between pimonidazole labelling and (18)F-FDG uptake suggests a positive relationship between hypoxia and increased glucose metabolism in this tumour model.


Assuntos
Anemia/metabolismo , Eritropoetina/uso terapêutico , Fluordesoxiglucose F18 , Glioma/metabolismo , Hipóxia/diagnóstico , Nitroimidazóis/metabolismo , Anemia/tratamento farmacológico , Animais , Autorradiografia , Eletrodos , Glioma/patologia , Hemoglobinas/análise , Humanos , Camundongos , Camundongos Nus , Músculo Esquelético/metabolismo , Transplante de Neoplasias , Proteínas Recombinantes , Transplante Heterólogo
20.
J Neurooncol ; 83(2): 111-9, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17443290

RESUMO

PURPOSE: Ferumoxtran-10 belongs to the Ultra Small Particles of Iron Oxide (USPIO) class of contrast agents and induces delayed tumor enhancement in brain tumors, reflecting the trapping of iron oxide particles by the macrophages and activated microglia. The aim of the study was to compare Ferumoxtran-10 contrast enhancement in four human high-grade glioma xenograft models (TCG2, TCG3, TCG4, and U87) with different growing profiles. MATERIALS AND METHODS: Fragments of human malignant glioma were orthotopically xenografted into the brain of four groups of nude mice. All mice underwent a MRI examination 24 h after intravenous administration of Ferumoxtran-10 (axial T1 SE weighted MR images). The contrast enhancement observed in the different tumor types was measured and was correlated to in vivo tumor growth and to histological parameters, such as proliferative tumor cell fraction, apoptosis, vascular density, and Perls' staining score. RESULTS: A good relationship was observed: (a) between tumor-to-background contrast and proliferative index, (b) between tumor-to-background contrast and tumor growth, and (c) between tumor-to-background contrast and Perls' staining score. The registered MR enhancement contrasts were not influenced by apoptotic index and by vascular density in these experimental xenografts. CONCLUSIONS: Tumor contrast enhancement 24 h after intravenous Ferumoxtran-10 administration seems to be well correlated to tumor proliferative index and tumor growth and could be used as an indirect marker of tumor proliferation.


Assuntos
Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Meios de Contraste/farmacocinética , Glioma/patologia , Ferro/farmacocinética , Óxidos/farmacocinética , Animais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Diferenciação Celular , Dextranos , Óxido Ferroso-Férrico , Glioma/diagnóstico por imagem , Glioma/metabolismo , Humanos , Imagem por Ressonância Magnética , Nanopartículas de Magnetita , Camundongos , Camundongos Nus , Índice Mitótico , Invasividade Neoplásica , Transplante de Neoplasias , Radiografia , Distribuição Tecidual , Transplante Heterólogo/patologia
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