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1.
Int J Clin Oncol ; 26(4): 647-658, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33575829

RESUMEN

PURPOSE: Effective treatment of diffuse intrinsic pontine glioma (DIPG) remains a formidable challenge due to inadequate penetration of the blood-brain barrier (BBB) by systemically administered chemotherapies. The BBB can be overcome by directly infusing drugs into pons using method of convection-enhanced delivery (CED). We describe our clinical experience and what we have learned about the safety and feasibility of treating DIPG with intermittent CED of carboplatin and sodium valproate to the pons through the Renishaw Drug Delivery System (RDDS). METHODS: Retrospective review (2017-2020) of children with DIPG, who following radiotherapy, received compassionate treatment commencing 3.3-10 months post-diagnosis (median 4.9 months). They received up to 7 cycles of 3-6 weekly pontine infusions of carboplatin (0.12-0.18 mg/ml) and sodium valproate (14.4-28.8 mg/ml). RESULTS: 13 children 3-19 years (mean 6.9 years) were treated. There were no surgical complications. With the exception of infusion channels blocking in one device, there were no adverse device effects. Two patients developed persistent 6th nerve palsies, which led to drug concentration reduction in the combination therapy. Subsequently infusion/ drug-related toxicities were transient. Tumour was controlled in pons in 10/13 patients. Median progression-free survival (PFS) was 13.0 months, while median overall survival (OS) was 15.3 months. CONCLUSIONS: Use of the RDDS was safe and well tolerated in all 13 patients. Treatment improved control of pontine disease resulting in longer PFS and OS and merits further evaluation in a clinical trial.


Asunto(s)
Antineoplásicos , Glioma Pontino Intrínseco Difuso , Glioma , Antineoplásicos/uso terapéutico , Carboplatino/efectos adversos , Niño , Convección , Glioma/tratamiento farmacológico , Glioma/radioterapia , Humanos , Puente , Estudios Retrospectivos , Ácido Valproico/efectos adversos , Adulto Joven
2.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(1): 69-74, 2021 Jan 30.
Artículo en Chino | MEDLINE | ID: mdl-33509755

RESUMEN

OBJECTIVE: To establish a mouse model bearing orthotopic temozolomide (TMZ)-resistant glioma that mimics the development of drug resistance in gliomas in vivo. METHODS: Seventy-eight adult C57BL/6 mice were randomly divided into 6 groups (n=13), including 3 TMZ induced groups with low, medium and high doses (5, 25, and 50 mg/kg, respectively) and 3 control groups. In each group, 5 mice were used for evaluating tumor size, 5 for observing survival, and 3 for collecting tumor tissues for primary cell culture. In low-dose TMZ induced group, 3 mice bearing orthotopic murine glioma GL261 cell xenografts received intraperitoneal injections of 5 mg/kg TMZ for 5 days followed by a 10-day washout period before collecting glioma tissues. Tumor cell suspensions were prepared and injected in the mice in the medium-dose group, which were treated with the same protocol but with an increased TMZ dose, and the tumor cells harvested from 3 mice were injected in the high-dose group. The mice bearing GL261 cell xenografts in the 3 control groups received no treatment or were injected with medium- or high-dose TMZ. Cell colony forming assay was used to assess TMZ resistance of each generation of the tumor cells; CCK8 assay was used to determine drug resistance index of the cells. RESULTS: The mouse models bearing TMZresistant glioma was successfully established. The cells from the high-dose induced group showed a significantly higher colony-forming rate than those from the high-dose control group (P < 0.05), and had a drug resistance 4.25 times higher than that of the cells from untreated control group. High-dose TMZ significantly reduced the tumor volume in the control group (P < 0.05) but not in the high-dose induced group (P < 0.01). The survival time of the tumor-bearing mice was significantly shortened in the high-dose induced group (P=0.0018). CONCLUSIONS: Progressive increase of TMZ doses in mice bearing orthotopic gliomas can effectively induce TMZ resistance of the gliomas.


Asunto(s)
Neoplasias Encefálicas , Glioma , Animales , Antineoplásicos Alquilantes/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Línea Celular Tumoral , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos , Glioma/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Temozolomida/farmacología , Temozolomida/uso terapéutico
3.
Gene ; 776: 145445, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33484758

RESUMEN

Glioblastom Multiforme (GBM) is the most invasive and malignant member of the IV grade of the subclass Astrocytoma according to the last assessment of the 2016 WHO report. Due to the resistance to treatment and weak response, as well as the topographical structure of the blood brain barrier, the treatment is also difficult due to the severe clinical manifestation, and new treatment methods and new therapeutic agents are needed. Temozolomide (TMZ) is widely used in the treatment of glioblastoma and is considered as the primary treatment modality. TMZ, a member of the class of cognitive agents, is currently considered the most effective drug because it can easily pass through the blood brain barrier. Glucose metabolism is a complex energy producing machine that, a glucose molecule produces 38 molecules of ATP after full glycolytic catabolism. According to Otto Warburg's numerous studies cancer cells perform the first glycolytic step without entering the mitochondrial step. These cells produce lactic acid and make the micro-media more acidic even in aerobic conditions. This phenomenon is attributed to the Warburg hypothesis and either as aerobic glycolysis. Although glycolysis enzymes are the primary actors of this phenotypic expression, some genetic and epigenetic factors are no exception. We experimentally used KC7F2 active ingredient to target cancer metabolism. In our study, we evaluated cancer metabolism in combination with the effect of TMZ chemotherapeutic agent, examining the effect of two different agents separately and in combination to observe the effects of cancer cell proliferation, survival, apoptosis and expression of metabolism genes on expression. We observed that the combined effect of reduced the effective dose of the TMZ alkylating agent and that the effect was increased and the effect of the combined teraphy is assessed from a metabolic point of view and that it suppresses aerobic glycolysis.


Asunto(s)
Disulfuros/farmacología , Glioma/tratamiento farmacológico , Sulfonamidas/farmacología , Temozolomida/farmacología , Antineoplásicos/farmacología , Antineoplásicos Alquilantes/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Disulfuros/metabolismo , Resistencia a Antineoplásicos/genética , Glioblastoma/patología , Glioma/patología , Glucosa/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Sulfonamidas/metabolismo , Temozolomida/metabolismo
4.
Anticancer Res ; 41(2): 619-633, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33517266

RESUMEN

BACKGROUND/AIM: The outlook for patients with high grade glioma (HGG) remains dismal. Hence, attention has focused on numerous innovative treatments. Our group has proposed a strategy on the use of a combination of polyphenols, as anti-invasive agents for the management of these neoplasms. MATERIALS AND METHODS: The aim of this study was to evaluate the in vitro effects of citrus flavonoids (tangeretin, nobiletin, naringin and limonin) and berry extracts (chokeberry, elderberry and bilberry) on selected mediators of invasion in 2 HGG cell cultures. RESULTS: The IC50 values could only be determined for tangeretin and chokeberry extract. The rest were non-functional in this context. Immunocytochemistry and flow cytometry results showed that chokeberry extract was most effective in down-regulating the expression of CD44. Similarly, RT-PCR data supported its ability to reduce gene expression of MMP-14 and EGFR. 2D invasion assays confirmed that inhibition is greater with chokeberry extract. CONCLUSION: Both polyphenols have anti-invasive potential but chokeberry extract is a stronger agent for glioma management.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Frutas , Glioma/tratamiento farmacológico , Extractos Vegetales/farmacología , Polifenoles/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Citrus , Receptores ErbB/genética , Receptores ErbB/metabolismo , Frutas/química , Glioma/genética , Glioma/metabolismo , Glioma/patología , Humanos , Metaloproteinasa 14 de la Matriz/genética , Metaloproteinasa 14 de la Matriz/metabolismo , Invasividad Neoplásica , Extractos Vegetales/aislamiento & purificación , Polifenoles/aislamiento & purificación , Prunus , Inhibidores Tisulares de Metaloproteinasas/genética , Inhibidores Tisulares de Metaloproteinasas/metabolismo , Vaccinium myrtillus
5.
Life Sci ; 270: 119113, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33508290

RESUMEN

AIMS: This study aimed to design and screen a dual functional fusion peptide that could penetrate the blood-brain barrier and target neuropilin 1 (NRP1) overexpressed in vascular endothelial cells for the anti-angiogenesis of glioma treatment. MAIN METHODS: At the cellular level, the in vitro anti-angiogenic activity of six NRP1 targeting peptides was screened by testing the ability to inhibit the proliferation and tube formation of HUVECs. Then, the in vitro anti-angiogenic activity of two fusion peptides containing different linkers was screened by testing the ability to inhibit HUVECs proliferation, tube formation and migration. The effect of fusion peptide on VEGFR2 related signal pathway was confirmed by Western-blotting. Surface plasmon resonance technology was used to detect the affinity of the fusion peptide to NRP1. The ability of FITC-labeled peptides to penetrate cells was confirmed by cell uptake assay. By establishing an orthotopic glioma model, we evaluated the ability of FITC-labeled peptides to penetrate the blood-brain barrier and their anti-glioma growth activity in vivo. KEY FINDINGS: We found that NRP1 targeting peptide RP7 and linker cysteine were the most suitable key components in the fusion peptide. We also found that the fusion peptide Tat-C-RP7 we constructed had the strongest ability to penetrate the blood-brain barrier and anti-angiogenic activity in vitro and in vivo. SIGNIFICANCE: At present, NRP1 targeting peptide as a drug delivery tool and molecular probe seems to have received more attention. We constructed a fusion peptide Tat-C-RP7 with strong anti-angiogenic activity for the treatment of glioma.


Asunto(s)
Glioma/metabolismo , Neuropilina-1/metabolismo , Péptidos/farmacología , Inhibidores de la Angiogénesis/farmacología , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/fisiología , Línea Celular Tumoral , China , Sistemas de Liberación de Medicamentos/métodos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Células Endoteliales/metabolismo , Femenino , Glioma/tratamiento farmacológico , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inmunoterapia , Liposomas/uso terapéutico , Ratones Endogámicos BALB C , Ratones Desnudos , Transducción de Señal/fisiología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo
6.
Adv Exp Med Biol ; 1283: 73-84, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33155139

RESUMEN

Diffuse intrinsic pontine glioma (DIPG) is a lethal midline brainstem tumor that most commonly occurs in children and is genetically defined by substitution of methionine for lysine at site 27 of histone 3 (H3K27M) in the majority of cases. This mutation has since been shown to exert an influence on the posttranslational epigenetic landscape of this disease, with the loss of trimethylation at lysine 27 (H3K27me3) the most common alteration. Based on these findings, a number of drugs targeting these epigenetic changes have been proposed, specifically that alter histone trimethylation, acetylation, or phosphorylation. Various mechanisms have been explored, including inhibition of H327 demethylase and methyltransferase to target trimethylation, inhibition of histone deacetylase (HDAC) and bromodomain and extraterminal (BET) to target acetylation, and inhibition of phosphatase-related enzymes to target phosphorylation. This chapter reviews the current rationales and progress made to date in epigenetically targeting DIPG via these mechanisms.


Asunto(s)
Neoplasias del Tronco Encefálico , Epigénesis Genética , Glioma , Histonas/genética , Neoplasias del Tronco Encefálico/genética , Niño , Glioma/tratamiento farmacológico , Glioma/genética , Histonas/metabolismo , Humanos , Mutación , Procesamiento Proteico-Postraduccional
7.
Biomed Pharmacother ; 133: 111058, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33378970

RESUMEN

Glioblastoma Multiforme (GBM) tumors contain a small population of glioma stem-like cells (GSCs) among the various differentiated GBM cells (d-GCs). GSCs drive tumor recurrence, and resistance to Temozolomide (TMZ), the standard of care (SoC) for GBM chemotherapy. In order to investigate a potential link between GSC specific mitochondria function and SoC resistance, two patient-derived GSC lines were evaluated for differences in their mitochondrial metabolism. In both the lines, GSCs had significantly lower mitochondrial -content, and -function compared to d-GCs. In vitro, the standard mitochondrial-specific inhibitors oligomycin A, antimycin A, and rotenone selectively inhibited GSC proliferation to a greater extent than d-GCs and human primary astrocytes. These findings indicate that mitochondrial inhibition can be a potential GSC-targeted therapeutic strategy in GBM with minimal off-target toxicity. Mechanistically the standard mitochondrial inhibitors elicit their GSC-selective cytotoxic effects through the induction of apoptosis or autophagy pathways. We tested for GSC proliferation in the presence of 3 safe FDA-approved drugs--trifluoperazine, mitoxantrone, and pyrvinium pamoate, all of which are also known mitochondrial-targeting agents. The SoC GBM therapeutic TMZ did not trigger cytotoxicity in glioma stem cells, even at 100 µM concentration. By contrast, trifluoperazine, mitoxantrone, and pyrvinium pamoate exerted antiproliferative effects in GSCs about 30-50 fold more effectively than temozolomide. Thus, we hereby demonstrate that FDA-approved mitochondrial inhibitors induce GSC-selective cytotoxicity, and targeting mitochondrial function could present a potential therapeutic option for GBM treatment.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Reposicionamiento de Medicamentos , Glioma/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Células Madre Neoplásicas/efectos de los fármacos , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica , Glioma/genética , Glioma/metabolismo , Glioma/patología , Humanos , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Transducción de Señal , Células Tumorales Cultivadas
8.
Neurocirugía (Soc. Luso-Esp. Neurocir.) ; 31(6): 268-278, nov.-dic. 2020. tab, graf
Artículo en Inglés | IBECS | ID: ibc-197921

RESUMEN

INTRODUCTION: It is common practice to prescribe prophylactic antiepileptic drugs (AED) to high-grade glioma (HGG) patients without a history of seizures, yet with limited evidence supporting its use. Ideally, the effectiveness of prophylactic anticonvulsants must outweigh the occurrence of adverse effects and interactions related to AED. The authors conducted a systematic review and metanalysis of longitudinal studies regarding the effectiveness of prophylactic AED in seizure-naïve HGG patients. MATERIALS AND METHODS: PubMed/MEDLINE, Cochrane Central Register of Controlled trials, Embase and clinicaltrials.gov databases were systematically searched. Of the initial 1773 studies identified, 15 were finally selected for data extraction and analysis. Heterogeneity among studies, pooled hazard ratios, publication bias and sensitivity analyses were performed separately for a 15-study group (HGG patients within larger series of brain tumors) and a 6-study group (exclusively HGG patients). RESULTS: AED prophylaxis did not significantly reduce the incidence of postoperative seizures compared with controls, both in the 15-study group (Mantel-Haenszel random-effects pooled OR 1.08, 95% CI 0.82-1.43, 2123 patients) and in the 6-study group (pooled OR 1.22, 95% CI 0.77-1.92, 540 patients). However, some issues (paucity of prospective trials, overall moderate-risk of bias, and few studies addressing HGG patients exclusively) preclude firm conclusions against routine prophylactic AED prescription. Reported adverse effects attributable to AED were acceptable in the majority of studies. CONCLUSIONS: Within the limitations of this review, the results of this metanalysis do not support the routine administration of prophylactic AED to HGG patients without a history of seizures


INTRODUCCIÓN: Generalmente se administran fármacos antiepilépticos (FAE) a pacientes con gliomas de alto grado (GAG) sin historia previa de crisis, a pesar de una escasa evidencia a favor. Idealmente la efectividad de la profilaxis anticomicial debe compensar la aparición de efectos adversos debidos a la medicación. Realizamos una revisión sistemática y un metaanálisis de estudios longitudinales respecto a la utilidad de los FAE en pacientes con GAG sin historia de crisis previa. MATERIAL Y MÉTODOS: Se revisaron las bases de datos PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, Embase y clinicaltrials.gov. De los 1.773 trabajos inicialmente identificados, 15 fueron seleccionados para la extracción de datos y análisis. Se realizaron análisis de heterogeneidad, sesgo de publicación, cálculo de OR combinadas y análisis de sensibilidad, por separado, en 2 grupos: grupo de 15 estudios (pacientes con GAG incluidos en series de tumores cerebrales) y grupo de 6 estudios (exclusivamente pacientes con GAG). RESULTADOS: La profilaxis con FAE no redujo de forma significativa la incidencia de crisis postoperatorias respecto a los controles, tanto en el grupo-15 (OR combinada de Mantel-Haenszel, efectos aleatorios de 1,08, IC 95%: 0,82-1,43, sobre 2.123 pacientes), como en el grupo-6 (OR combinada de 1,22, IC 95% 0,77-1,92, sobre 540 pacientes). Sin embargo, la escasez de ensayos aleatorizados y de estudios con GAG exclusivamente, junto a un sesgo global moderado, impiden establecer una recomendación sólida contra la profilaxis anticomicial. Los efectos adversos atribuidos a los FAE fueron aceptables en la mayoría de los estudios. CONCLUSIONES: Dentro de las limitaciones de esta revisión, los resultados del metaanálisis no apoyan el uso rutinario de profilaxis antiepiléptica en pacientes con GAG sin historia previa de crisis


Asunto(s)
Humanos , Anticonvulsivantes/uso terapéutico , Glioma/tratamiento farmacológico , Profilaxis Pre-Exposición/métodos , Anticonvulsivantes/efectos adversos , Convulsiones/prevención & control , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/complicaciones , Glioma/cirugía , Estudios Longitudinales , Convulsiones/etiología , Cuidados Posoperatorios/métodos , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/cirugía
9.
Neurocirugía (Soc. Luso-Esp. Neurocir.) ; 31(6): 289-298, nov.-dic. 2020.
Artículo en Español | IBECS | ID: ibc-197923

RESUMEN

INTRODUCCIÓN: El tratamiento de los glioblastomas (GMB) comienza en la mayor parte de los pacientes con una cirugía, ya sea para la extirpación tumoral, ya sea para la obtención de tejido con el que determinar un diagnóstico histológico. Con el fin de obtener el máximo beneficio de estos tratamientos cada paciente debe ser valorado de forma individualizada por un equipo multidisciplinar, constituido por aquellas especialidades involucradas tanto en el diagnóstico como en el tratamiento. MATERIAL Y MÉTODOS: El objetivo de este trabajo es elaborar unas recomendaciones de tratamiento para los pacientes con GBM, para lo cual un experto en cada campo ha descrito lo más relevante de dicha área basado tanto en su experiencia como en la literatura. RESULTADOS: Se han desarrollado los distintos apartados sobre el tratamiento de los GBM y al final de cada apartado se concluye la recomendación del GTNO. CONCLUSIONES: A pesar de que los GBM son tumores agresivos y el pronóstico es malo, los pacientes se pueden beneficiar de tratamientos que mejoren no solo la supervivencia global sino también la calidad de vida. El neurocirujano debe conocer las distintas opciones de tratamientos, sus indicaciones y riesgos para poder participar activamente en la toma de decisiones y ofrecer un tratamiento neuroquirúrgico oportuno a cada situación


INTRODUCTION: Glioblastoma (GBM) treatment starts in most patients with surgery, either resection surgery or biopsy, to reach a histology diagnose. Multidisciplinar team, including specialists in brain tumors diagnose and treatment, must make an individualize assessment to get the maximum benefit of the available treatments. MATERIAL AND METHODS: Experts in each GBM treatment field have briefly described it based in their experience and the reviewed of the literature. RESULTS: Each area has been summarized and the consensus of the brain tumor group has been included at the end. CONCLUSIONS: GBM are aggressive tumors with a dismal prognosis, however accurate treatments can improve overall survival and quality of life. Neurosurgeons must know treatment options, indications and risks to participate actively in the decision making and to offer the best surgical treatment in every case


Asunto(s)
Humanos , Conferencias de Consenso como Asunto , Retinoblastoma/terapia , Grupo de Atención al Paciente/normas , Neoplasias Encefálicas/cirugía , Toma de Decisiones , Sociedades Médicas/normas , Glioma/radioterapia , Glioma/cirugía , Glioma/tratamiento farmacológico , Monitorización Neurofisiológica Intraoperatoria/normas , Inmunoterapia/normas
10.
Int J Mol Sci ; 21(24)2020 Dec 17.
Artículo en Inglés | MEDLINE | ID: mdl-33348922

RESUMEN

In this review, we discuss the molecular characteristics, development, evolution, and therapeutic perspectives for pediatric high-grade glioma (pHGG) arising in cerebral hemispheres. Recently, the understanding of biology of pHGG experienced a revolution with discoveries arising from genomic and epigenomic high-throughput profiling techniques. These findings led to identification of prevalent molecular alterations in pHGG and revealed a strong connection between epigenetic dysregulation and pHGG development. Although we are only beginning to unravel the molecular biology underlying pHGG, there is a desperate need to develop therapies that would improve the outcome of pHGG patients, as current therapies do not elicit significant improvement in median survival for this patient population. We explore the molecular and cell biology and clinical state-of-the-art of pediatric high-grade gliomas (pHGGs) arising in cerebral hemispheres. We discuss the role of driving mutations, with a special consideration of the role of epigenetic-disrupting mutations. We will also discuss the possibilities of targeting unique molecular vulnerabilities of hemispherical pHGG to design innovative tailored therapies.


Asunto(s)
Biomarcadores de Tumor/antagonistas & inhibidores , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Terapia Molecular Dirigida , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Niño , Glioma/genética , Glioma/patología , Humanos , Clasificación del Tumor
11.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 5029-5032, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-33019116

RESUMEN

We have recently reported encapsulating an antitumor iron chelator, Dp44mT (Di-2-pyridylketone-4,4dimethyl-3-thiosemicarbazone), in nanoparticles (NPs) of poly(lactic-co-glycolic acid) (PLGA). In this paper, we examine the effectiveness of this nano-formulation, referred to as Dp44mT-NPs, against several cancer cell lines in vitro; specifically, we evaluate the cytotoxicity of this formulation in glioma (U87, U251), breast (MCF7), and colorectal (HT29) cancer cell lines. Cell viability results from treatment of glioma cells with Dp44mT-NPs for 24-72 hrs revealed that these NPs were highly toxic towards these malignant cells with very low IC50 values (<100 nM). Although addition of a PEG (poly(ethylene glycol)) layer to the surface of NPs reduced their toxicity in glioma cells, they remained highly toxic towards these cells (IC50 of 135-210 nM). Dp44mT-NPs were also toxic towards breast MCF7 and colorectal HT29 cells, but at higher dosages (IC50 >1 µM) compared to glioma cells. Addition of PEG to these NPs, again lowered their toxicity in these cells. Varying the percentage of PEG on NPs resulted in changes in their cytotoxicity, highlighting the necessity of further optimization of this parameter. This study, overall, demonstrates the therapeutic potential of Dp44mT-NPs against different malignant cells, with particularly promising results in highly-aggressive glioma tumor cells.


Asunto(s)
Glioma , Nanopartículas , Tiosemicarbazonas , Glioma/tratamiento farmacológico , Humanos , Polietilenglicoles , Tiosemicarbazonas/farmacología
12.
Anticancer Res ; 40(11): 6473-6484, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33109586

RESUMEN

BACKGROUND/AIM: Glioblastoma multiforme (GBM) is an intractable tumor that has a very poor prognosis despite intensive treatment with temozolomide plus radiotherapy. PATIENTS AND METHODS: Sixteen newly diagnosed patients with high-grade gliomas were enrolled in a phase II study of the α-type-1 DC vaccine. Briefly, DCs obtained from the culture of enriched monocytes in the presence of a cytokine cocktail, were pulsed with a cocktail of 5 synthetic peptides and cryopreserved until injection into patients. RESULTS: The amount of IL-12 produced by activated DCs was higher than that previously reported. Among 15 evaluable patients, 10 showed positive CTL responses to any peptides in an ELISPOT assay. After 6 years of observation, five patients were still alive, and two of these patients were relapse-free. Moreover, a significant survival-prolonging effect was verified in DC-treated glioma patients. CONCLUSION: Peptide-cocktail-pulsed α-type-1 DC vaccines have a potential therapeutic effect on survival when used in combination with the standard regimen, which is partly based on IL-12-IFN-γ-mediated T-cell activation.


Asunto(s)
Vacunas contra el Cáncer/administración & dosificación , Células Dendríticas/inmunología , Glioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Vacunas contra el Cáncer/inmunología , Polaridad Celular/inmunología , Supervivencia sin Enfermedad , Femenino , Glioma/inmunología , Glioma/patología , Humanos , Interferón gamma/genética , Interleucina-12/genética , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/patología , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Linfocitos T/inmunología , Vacunación/métodos
13.
Anticancer Res ; 40(10): 5427-5436, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32988864

RESUMEN

BACKGROUND/AIM: The tetrazolium-based MTT cytotoxicity assay is well established for screening putative anti-cancer agents. However, it has limitations including lack of reproducibility with glioma cells treated with polyphenols. The aim of this study was to evaluate whether a flow cytometric assay with the anthraquinone, DRAQ7, was a better alternative than the colorimetric MTT assay for measuring cell viability. MATERIALS AND METHODS: Two glioma cell lines (IPSB-18, U373) and 1 pancreatic cancer cell line (AsPC-1) were treated with 4 polyphenols, namely red grape seed extract, red clover extract, anthocyanin-rich extract and curcumin. Cell viability was assessed using MTT assay and DRAQ7 staining. RESULTS: Limitations of MTT assay included lack of sensitivity and interference with the structure and absorbance spectra of polyphenols. Also, DMSO was toxic to glioma cells. Microscopic observations of cells treated with polyphenols confirmed the range of IC50 values evaluated by DRAQ7, but not by the MTT assay. CONCLUSION: DRAQ7 is a better alternative than MTT for measuring viability of glioma cells treated with brightly coloured polyphenols.


Asunto(s)
Antraciclinas/farmacología , Supervivencia Celular/efectos de los fármacos , Glioma/tratamiento farmacológico , Polifenoles/farmacología , Antraciclinas/química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Glioma/patología , Humanos , Concentración 50 Inhibidora , Sales de Tetrazolio/química , Tiazoles/química
14.
Medicine (Baltimore) ; 99(38): e22238, 2020 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-32957367

RESUMEN

BACKGROUND: Systematic evaluation of the effectiveness and safety of combined procarbazine, lomustine, and vincristine for treating recurrent high-grade glioma. METHODS: Electronic databases including PubMed, MEDLINE, EMBASE, Cochrane Library Central Register of Controlled Trials, WanFang, and China National Knowledge Infrastructure (CNKI) were used to search for studies related to the utilization of combined procarbazine, lomustine, and vincristine as a therapeutic method for recurrent high-grade glioma. Literature screening, extraction of data, and evaluation of high standard studies were conducted by 2 independent researchers. The robustness and strength of the effectiveness and safety of combined procarbazine, lomustine, and vincristine as a therapeutic methodology for recurrent high-grade glioma was assessed based on the odds ratio (OR), mean differences (MDs), and 95% confidence interval (CI). RevMan 5.3 software was used for carrying out the statistical analysis. RESULTS: These results obtained in this study will be published in a peer-reviewed journal. CONCLUSION: Evidently, the conclusion of this study will provide an assessment on whether combined procarbazine, lomustine, and vincristine provides an effective and safe form of treatment for recurrent high-grade glioma. SYSTEMATIC REVIEW REGISTRATION NUMBER: INPLASY202080078.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Metaanálisis como Asunto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Revisiones Sistemáticas como Asunto , Adolescente , Adulto , Neoplasias Encefálicas/patología , Glioma/patología , Humanos , Lomustina/efectos adversos , Lomustina/uso terapéutico , Clasificación del Tumor , Recurrencia Local de Neoplasia/patología , Procarbazina/efectos adversos , Procarbazina/uso terapéutico , Vincristina/efectos adversos , Vincristina/uso terapéutico , Adulto Joven
15.
PLoS One ; 15(9): e0238238, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32881880

RESUMEN

The prognosis for patients with glioblastoma (GB) remains grim. Concurrent temozolomide (TMZ) radiation-the cornerstone of glioma control-extends the overall median survival of GB patients by only a few months over radiotherapy alone. While these survival gains could be partly attributed to radiosensitization, this benefit is greatly minimized in tumors expressing O6-methylguanine DNA methyltransferase (MGMT), which specifically reverses O6-methylguanine lesions. Theoretically, non-O6-methylguanine lesions (i.e., the N-methylpurine adducts), which represent up to 90% of TMZ-generated DNA adducts, could also contribute to radiosensitization. Unfortunately, at concentrations attainable in clinical practice, the alkylation capacity of TMZ cannot overwhelm the repair of N-methylpurine adducts to efficiently exploit these lesions. The current therapeutic application of TMZ therefore faces two main obstacles: (i) the stochastic presence of MGMT and (ii) a blunted radiosensitization potential at physiologic concentrations. To circumvent these limitations, we are developing a novel molecule called NEO212-a derivatization of TMZ generated by coupling TMZ to perillyl alcohol. Based on gas chromatography/mass spectrometry and high-performance liquid chromatography analyses, we determined that NEO212 had greater tumor cell uptake than TMZ. In mouse models, NEO212 was more efficient than TMZ at crossing the blood-brain barrier, preferentially accumulating in tumoral over normal brain tissue. Moreover, in vitro analyses with GB cell lines, including TMZ-resistant isogenic variants, revealed more potent cytotoxic and radiosensitizing activities for NEO212 at physiologic concentrations. Mechanistically, these advantages of NEO212 over TMZ could be attributed to its enhanced tumor uptake presumably leading to more extensive DNA alkylation at equivalent dosages which, ultimately, allows for N-methylpurine lesions to be better exploited for radiosensitization. This effect cannot be achieved with TMZ at clinically relevant concentrations and is independent of MGMT. Our findings establish NEO212 as a superior radiosensitizer and a potentially better alternative to TMZ for newly diagnosed GB patients, irrespective of their MGMT status.


Asunto(s)
Dacarbazina/análogos & derivados , Resistencia a Antineoplásicos , Glioma/tratamiento farmacológico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Temozolomida/uso terapéutico , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Dacarbazina/análisis , Dacarbazina/metabolismo , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Resistencia a Antineoplásicos/genética , Cromatografía de Gases y Espectrometría de Masas , Glioma/patología , Humanos , Ratones , Ratones Endogámicos C57BL , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , Fármacos Sensibilizantes a Radiaciones/análisis , Fármacos Sensibilizantes a Radiaciones/metabolismo , Fármacos Sensibilizantes a Radiaciones/farmacología , Temozolomida/análisis , Temozolomida/metabolismo , Temozolomida/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Life Sci ; 260: 118411, 2020 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-32918978

RESUMEN

AIMS: Cell adhesion mediated-drug resistance (CAM-DR) is one of main reasons for. the limitation to chemotherapy, but the underlying mechanism remains unclear in glioma. In this study, we investigated the mechanism of CAM-DR induced by Fibronectin (Fn). Besides, we studied the reversal effect of Oroxylin A, a natural flavonoid extracted from Scutellaria radix, on Temozolomide (TMZ) insensitivity of glioma cells. MAIN METHODS: Human Fn protein was used to mimic cell adhesion model and investigate its effect on the insensitivity of glioma cells to TMZ. Moreover, Oroxylin A was studied regarding its reversal effect on TMZ insensitivity of glioma via multiple molecular biological methods such as MTT, cell apoptosis assay, siRNA transfection, western blot, immunofluorescence assay. KEY FINDINGS: Fn could decrease the apoptosis-inducing effect of TMZ and led to the CAM-DR in glioma cells. Further studies showed that up-regulations of IP3R1 and intracellular Ca2+ level induced the activation of AKT kinase which increased the phosphorylation of GSK-3ß and subsequently caused the entry of ß-catenin into the nucleus. Knocking down IP3R1 significantly improved the sensitivity of glioma cells to TMZ. Meanwhile, after treatment with low-toxic concentration of Oroxylin A, the apoptosis induced by TMZ under Fn condition increased dramatically. Furthermore, our results revealed that Oroxylin A markedly inhibited the expression of IP3R1 and the activation of AKT/ß-catenin pathway. SIGNIFICANCE: Oroxylin A could reverse the insensitivity of TMZ via suppressing IP3R1/AKT/ß-catenin pathway and it might be helpful for enhancing the anti-cancer effect of TMZ in glioma.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Fibronectinas/efectos adversos , Flavonoides/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioma/tratamiento farmacológico , Temozolomida/farmacología , Animales , Antineoplásicos Alquilantes/farmacología , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Femenino , Glioma/etiología , Glioma/metabolismo , Glioma/patología , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , beta Catenina/genética , beta Catenina/metabolismo
17.
Nat Commun ; 11(1): 3883, 2020 08 04.
Artículo en Inglés | MEDLINE | ID: mdl-32753598

RESUMEN

Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that the MGMT genomic rearrangements contribute to TMZ resistance both in vitro and in vivo. Lastly, we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Resistencia a Antineoplásicos/genética , Reordenamiento Génico , Glioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Temozolomida/farmacología , Proteínas Supresoras de Tumor/genética , Adolescente , Adulto , Anciano , Animales , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Aductos de ADN/efectos de los fármacos , Aductos de ADN/metabolismo , Metilación de ADN , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Glioma/genética , Humanos , Masculino , Ratones , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Regiones Promotoras Genéticas/genética , RNA-Seq , Temozolomida/uso terapéutico , Proteínas Supresoras de Tumor/metabolismo , Regulación hacia Arriba , Secuenciación Completa del Genoma , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto Joven
18.
Medicine (Baltimore) ; 99(28): e21147, 2020 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-32664146

RESUMEN

High-grade gliomas (HGGs) are a rapidly progressive and highly recurrent group of primary brain tumors. Despite aggressive surgical resection with chemoradiotherapy, prognoses remained poor. Valproic acid (VPA), a histone deacetylase inhibitor has shown the potential to inhibit glioma cell growth in vitro through several diverse mechanisms. However clinical studies regarding the effect of VPA on HGGs are limited. This study aimed to investigate whether using VPA in patients with HGGs under temozolomide (TMZ) would lead to a better overall survival (OS).We used the Taiwan National Health Insurance Research database to conduct this population-based cohort study. A total of 2379 patients with HGGs under TMZ treatment were included and were further classified into VPA (n = 1212, VPA ≥ 84 defined daily dose [DDD]) and non-VPA (n = 1167, VPA < 84 DDD) groups. Each patient was followed from 1998 to 2013 or until death. A Cox proportional hazard regression was performed to evaluate the effect of VPA and OS.The VPA group had a longer mean OS time compared with the non-VPA group (OS: 50.3 ±â€Š41.0 vs 42.0 ±â€Š37.2 months, P < .001). In patients between 18 and 40 years old, the difference is most significant (OS: 70.5 ±â€Š48.7 vs 55.1 ±â€Š46.0, P = .001). The adjusted hazard ratio is 0.81 (95% confidence interval, 0.72-0.91) for the VPA group relative to the non-VPA group.VPA at over 84 DDD improved OS in HGGs TMZ treatment.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Estadificación de Neoplasias , Vigilancia de la Población/métodos , Temozolomida/uso terapéutico , Ácido Valproico/uso terapéutico , Adolescente , Adulto , Anciano , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidad , Inhibidores Enzimáticos/uso terapéutico , Femenino , Estudios de Seguimiento , Glioma/diagnóstico , Glioma/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Taiwán/epidemiología , Adulto Joven
20.
Korean J Radiol ; 21(7): 908-918, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32524791

RESUMEN

OBJECTIVE: To categorize the radiological patterns of recurrence after bevacizumab treatment and to derive the pooled proportions of patients with recurrent malignant glioma showing the different radiological patterns. MATERIALS AND METHODS: A systematic literature search in the Ovid-MEDLINE and EMBASE databases was performed to identify studies reporting radiological recurrence patterns in patients with recurrent malignant glioma after bevacizumab treatment failure until April 10, 2019. The pooled proportions according to radiological recurrence patterns (geographically local versus non-local recurrence) and predominant tumor portions (enhancing tumor versus non-enhancing tumor) after bevacizumab treatment were calculated. Subgroup and meta-regression analyses were also performed. RESULTS: The systematic review and meta-analysis included 17 articles. The pooled proportions were 38.3% (95% confidence interval [CI], 30.6-46.1%) for a geographical radiologic pattern of non-local recurrence and 34.2% (95% CI, 27.3-41.5%) for a non-enhancing tumor-predominant recurrence pattern. In the subgroup analysis, the pooled proportion of non-local recurrence in the patients treated with bevacizumab only was slightly higher than that in patients treated with the combination with cytotoxic chemotherapy (34.9% [95% CI, 22.8-49.4%] versus 22.5% [95% CI, 9.5-44.6%]). CONCLUSION: A substantial proportion of high-grade glioma patients show non-local or non-enhancing radiologic patterns of recurrence after bevacizumab treatment, which may provide insight into surrogate endpoints for treatment failure in clinical trials of recurrent high-grade glioma.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Glioma/diagnóstico por imagen , Glioma/patología , Humanos , Imagen por Resonancia Magnética , Clasificación del Tumor , Recurrencia Local de Neoplasia
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