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1.
Anticancer Res ; 40(10): 5801-5806, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988908

RESUMO

BACKGROUND/AIM: Whether adding tumor treating fields (TTF) to the Stupp protocol increases survival for glioblastoma (GBM) patients in routine clinical care remains unknown. PATIENTS AND METHODS: We retrospectively identified adult patients with newly diagnosed GBM (n=104) treated with the Stupp protocol or TTF at our Institution. RESULTS: Thirty-six percent (37/104) of patients received TTF in conjunction with the Stupp protocol and these patients had increased 6-month (p=0.006) and 1-year (p=0.170), but not 2-year survival rates compared to the 67-patients who received Stupp alone. The improvement of survival rate at 6-month was further confirmed by a modified Poisson model (p=0.010). However, we did not observe any improvement in overall survival (OS) with a Cox model. CONCLUSION: While adding TTF to the Stupp protocol appeared to benefit patients with newly diagnosed GBM, this effect was mild and may be largely due to selection bias.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/patologia , Terapia Combinada , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Intervalo Livre de Doença , Feminino , Glioblastoma/epidemiologia , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Temozolomida/administração & dosagem , Temozolomida/efeitos adversos , Resultado do Tratamento
2.
Life Sci ; 258: 118158, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32750435

RESUMO

AIMS: Glioblastoma multiforme (GBM) is characterized by aggressive infiltration and terrible lethality. The overwhelming majority of chemotherapeutic drugs fail to exhibit the desired treatment effects. Polydatin (PD), which was initially extracted from Polygonum cuspidatum, is distinguished for its outstanding cardioprotective, hepatoprotective, and renal protective effects, as well as significant anticancer activities. However, the anti-GBM effect of PD is unclear. MATERIALS AND METHODS: Cell proliferation and apoptosis after PD intervention were estimated using MTT, colony formation and flow cytometry assays in vitro, while wound-healing and Transwell assays were applied to assess cell migration and invasion. In addition, the anti-GBM effects of PD in vivo were detected in the subcutaneous tumor model of nude mice. Moreover, Western blot, immunofluorescence and immunohistochemical staining assays were employed to elaborate the relevant molecular mechanisms. KEY FINDINGS: The present study demonstrated that PD repressed cell proliferation, migration, invasion and stemness and promoted apoptosis in GBM cells. Moreover, by correlating the molecular characteristics of cancer cells with different sensitivities to PD and employing diverse analytical methods, we ultimately verified that the cytotoxicity of PD was related to EGFR-AKT/ERK1/2/STAT3-SOX2/Snail signaling pathway inhibition, in which multiple components were vital therapeutic targets of GBM. SIGNIFICANCE: This work demonstrated that PD could inhibit proliferation, migration, invasion and stemness and induce apoptosis by restraining multiple components of the EGFR-AKT/ERK1/2/STAT3-SOX2/Snail signaling pathway in GBM cells.


Assuntos
Antineoplásicos/uso terapêutico , Glioblastoma/tratamento farmacológico , Glucosídeos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Estilbenos/uso terapêutico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Glioblastoma/metabolismo , Glucosídeos/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Fator de Transcrição STAT3/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Estilbenos/farmacologia
3.
Anticancer Res ; 40(8): 4237-4244, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727750

RESUMO

BACKGROUND/AIM: To study the changes of glioblastoma multiforme during chemoradiotherapy (CRT) and to evaluate the impact of changes on dosimetry and clinical outcomes. PATIENTS AND METHODS: Forty-three patients underwent volumetric imaging-based replanning. Prognostic factors and gross tumor volume changes in relation to overall survival and the effect of adaptive replanning were statistically analyzed. RESULTS: Patients with total tumor removal, with shorter time to CRT (<27 days), with methylated O-6 methylguanine DNA methyltransferase and good performance status (>60%) had better survival. Tumor shrinkage in 24 patients resulted in improved survival compared to 19 in whom tumor was unchanged or progressed (25.3 vs. 11.1 months, p=0.04). Adapted planning target volume allowed a reduction in irradiated volume, while increasing survival (12.06 vs. 28.98 months, p=0.026). CONCLUSION: Tumor response during CRT has significant impact on the outcome. Adaptation of the planning target volume to the tumor changes proved to be beneficial and warrants further investigation.


Assuntos
Neoplasias Encefálicas/radioterapia , Glioblastoma/radioterapia , Planejamento da Radioterapia Assistida por Computador/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/tratamento farmacológico , Quimiorradioterapia/métodos , Criança , Pré-Escolar , Feminino , Glioblastoma/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
4.
Life Sci ; 257: 118027, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622951

RESUMO

AIM: Glioblastoma is an extremely aggressive glioma, resistant to radio and chemotherapy usually performed with temozolomide. One of the main reasons for glioblastoma resistance to conventional therapies is due to the presence of cancer stem-like cells. These cells could recapitulate some signaling pathways important for embryonic development, such as Sonic hedgehog. Here, we investigated if the inhibitor of the Sonic hedgehog pathway, cyclopamine, could potentiate the temozolomide effect in cancer stem-like cells and glioblastoma cell lines in vitro. MAIN METHODS: The viability of glioblastoma cells exposed to cyclopamine and temozolomide treatment was evaluated by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay while the induction of apoptosis was assessed by western blot. The stemness properties of glioma cells were verified by clonogenic and differentiation assay and the expression of stem cell markers were measured by fluorescence microscopy and western blot. KEY FINDINGS: The glioblastoma viability was reduced by cyclopamine treatment. Cyclopamine potentiated temozolomide treatment in glioblastoma cell lines by inducing apoptosis through activation of caspase-3 cleaved. Conversely, the combined treatment of cyclopamine and temozolomide potentiated the stemness properties of glioblastoma cells by inducing the expression of SOX-2 and OCT-4. SIGNIFICANCE: Cyclopamine plays an effect on glioblastoma cell lines but also sensibilize them to temozolomide treatment. Thus, first-line treatment with Sonic hedgehog inhibitor followed by temozolomide could be used as a new therapeutic strategy for glioblastoma patients.


Assuntos
Glioblastoma/metabolismo , Proteínas Hedgehog/metabolismo , Alcaloides de Veratrum/farmacologia , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Proteínas Hedgehog/efeitos dos fármacos , Proteínas Hedgehog/fisiologia , Humanos , Células-Tronco Neoplásicas/metabolismo , Fator 3 de Transcrição de Octâmero , Fatores de Transcrição SOXB1 , Transdução de Sinais/efeitos dos fármacos , Temozolomida/farmacologia , Alcaloides de Veratrum/metabolismo
5.
PLoS One ; 15(7): e0219632, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32706829

RESUMO

INTRODUCTION: Surgical resection and systemic chemotherapy with temozolomide remain the mainstay for treatment of glioblastoma. However, many patients are not candidates for surgical resection given inaccessible tumor location or poor health status. Furthermore, despite being first line treatment, temozolomide has only limited efficacy. METHODS: The development of injectable hydrogel-based carrier systems allows for the delivery of a wide range of chemotherapeutics that can achieve high local concentrations, thus potentially avoiding systemic side effects and wide-spread neurotoxicity. To test this modality in a realistic environment, we developed a diblock copolypeptide hydrogel (DCH) capable of carrying and releasing paclitaxel, a compound that we found to be highly potent against primary gliomasphere cells. RESULTS: The DCH produced minimal tissue reactivity and was well tolerated in the immune-competent mouse brain. Paclitaxel-loaded hydrogel induced less tissue damage, cellular inflammation and reactive astrocytes than cremaphor-taxol (typical taxol-carrier) or hydrogel alone. In a deep subcortical xenograft model of glioblastoma in immunodeficient mice, injection of paclitaxel-loaded hydrogel led to local tumor control and improved survival. However, the tumor cells were highly migratory and were able to eventually escape the area of treatment. CONCLUSIONS: These findings suggest this technology may be ultimately applicable to patients with deep-seated inoperable tumors, but as currently formulated, complete tumor eradication would be highly unlikely. Future studies should focus on targeting the migratory potential of surviving cells.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Glioblastoma/tratamento farmacológico , Hidrogéis/química , Paclitaxel/uso terapêutico , Peptídeos/química , Animais , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Sistema Nervoso Central/patologia , Portadores de Fármacos/química , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Paclitaxel/química , Taxa de Sobrevida , Temozolomida/química , Temozolomida/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Life Sci ; 256: 117943, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32531377

RESUMO

AIM: The aim of this study was to improve the therapeutic index of chemotherapeutic drugs on glioblastoma cells through an improved co-drug delivery system. MATERIALS AND METHODS: Methotrexate (MTX) and paclitaxel (PTX) were co-loaded into poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) coated with polyvinyl alcohol (PVA) and Poloxamer188 (P188). KEY FINDINGS: The mean size of the NPs was about 212 nm, with a zeta potential of about -15.7 mV. Encapsulation efficiency (EE%) and drug loading (DL%) were determined to be 72% and 4% for MTX and 85% and 4.9% for PTX, respectively. The prepared NPs were characterized by differential thermal analysis (DTA) and thermogravimetric analysis (TGA). Moreover, an in vitro sustained release profile was observed for both drug loaded PLGA NPs. Glioblastoma cellular uptake of the NPs was confirmed by fluorescence microscopy and cell survival rate was investigated through the 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method after 48 h of incubation showing IC50 values of 24.5 µg·mL-1 for PTX and 9.5 µg·mL-1 for MTX for the MTX/PTX co-loaded PLGA nanoparticles coated with PVA/P188 (Co-2 NPs). Apoptosis and necrosis were also studied via flow cytometry, the lactate dehydrogenase (LDH) assay and the amount of anti-apoptotic protein (Bcl-2) expression. Blood compatibility of the co-delivery of PTX and MTX loaded PLGA NPs was investigated using a hemolysis method as well. SIGNIFICANCE: The co-delivery of PTX and MTX loaded PLGA NPs is promising for the treatment of glioblastoma compared to their respective free drug formulations and, thus, should be further investigated.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Composição de Medicamentos , Glioblastoma/tratamento farmacológico , Metotrexato/uso terapêutico , Nanopartículas/química , Paclitaxel/uso terapêutico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Antineoplásicos/farmacologia , Apolipoproteínas/metabolismo , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Glioblastoma/patologia , Hemólise/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , L-Lactato Desidrogenase/metabolismo , Metotrexato/farmacologia , Nanopartículas/ultraestrutura , Paclitaxel/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos
7.
Proc Natl Acad Sci U S A ; 117(22): 12324-12331, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32409605

RESUMO

Glioblastoma multiforme (GBM) is an aggressive cancer without currently effective therapies. Radiation and temozolomide (radio/TMZ) resistance are major contributors to cancer recurrence and failed GBM therapy. Heat shock proteins (HSPs), through regulation of extracellular matrix (ECM) remodeling and epithelial mesenchymal transition (EMT), provide mechanistic pathways contributing to the development of GBM and radio/TMZ-resistant GBM. The Friend leukemia integration 1 (Fli-1) signaling network has been implicated in oncogenesis in GBM, making it an appealing target for advancing novel therapeutics. Fli-1 is linked to oncogenic transformation with up-regulation in radio/TMZ-resistant GBM, transcriptionally regulating HSPB1. This link led us to search for targeted molecules that inhibit Fli-1. Expression screening for Fli-1 inhibitors identified lumefantrine, an antimalarial drug, as a probable Fli-1 inhibitor. Docking and isothermal calorimetry titration confirmed interaction between lumefantrine and Fli-1. Lumefantrine promoted growth suppression and apoptosis in vitro in parental and radio/TMZ-resistant GBM and inhibited tumor growth without toxicity in vivo in U87MG GBM and radio/TMZ-resistant GBM orthotopic tumor models. These data reveal that lumefantrine, an FDA-approved drug, represents a potential GBM therapeutic that functions through inhibition of the Fli-1/HSPB1/EMT/ECM remodeling protein networks.


Assuntos
Antimaláricos/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Lumefantrina/administração & dosagem , Temozolomida/administração & dosagem , Neoplasias Encefálicas/radioterapia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/radioterapia , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Transativadores/genética , Transativadores/metabolismo
8.
Int J Nanomedicine ; 15: 2789-2808, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368055

RESUMO

Glioblastoma (GB) is a grade IV astrocytoma that maintains a poor prognosis with respect to current treatment options. Despite major advancements in the fields of surgery and chemoradiotherapy over the last few decades, the life expectancy for someone with glioblastoma remains virtually unchanged and warrants a new approach for treatment. Poly(amidoamine) (PAMAM) dendrimers are a type of nanomolecule that ranges in size (between 1 and 100 nm) and shape and can offer a new viable solution for the treatment of intracranial tumors, including glioblastoma. Their ability to deliver a variety of therapeutic cargo and penetrate the blood-brain barrier (BBB), while preserving low cytotoxicity, make them a favorable candidate for further investigation into the treatment of glioblastoma. Here, we present a systematic review of the current advancements in PAMAM dendrimer technology, including the wide spectrum of dendrimer generations formulated, surface modifications, core modifications, and conjugations developed thus far to enhance tumor specificity and tumor penetration for treatment of glioblastoma. Furthermore, we highlight the extensive variety of therapeutics capable of delivery by PAMAM dendrimers for the treatment of glioblastoma, including cytokines, peptides, drugs, siRNAs, miRNAs, and organic polyphenols. While there have been prolific results stemming from aggressive research into the field of dendrimer technology, there remains a nearly inexhaustible amount of questions that remain unanswered. Nevertheless, this technology is rapidly developing and is nearing the cusp of use for aggressive tumor treatment. To that end, we further highlight future prospects in focus as researchers continue developing more optimal vehicles for the delivery of therapeutic cargo.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Dendrímeros/química , Sistemas de Liberação de Medicamentos/métodos , Glioblastoma/tratamento farmacológico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Dendrímeros/uso terapêutico , Humanos
9.
Int J Nanomedicine ; 15: 2935-2945, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32425525

RESUMO

Background: New anticancer agents that rely on natural/healthy, not synthetic/toxic, components are very much needed. Methods: Ricinoleyl hydroxamic acid (RHA) was synthesized from castor oil and hydroxylamine using Lipozyme TL IM as a catalyst. To optimize the conversion, the effects of the following parameters were investigated: type of organic solvent, period of reaction, amount of enzyme, the molar ratio of reactants and temperature. The highest conversion was obtained when the reaction was carried out under the following conditions: hexane as a solvent; reaction period of 48 hours; 120 mg of Lipozyme TL IM/3 mmol oil; HA-oil ratio of 19 mmol HA/3 mmol oil; and temperature of 40°C. The cytotoxicity of the synthesized RHA was assessed using human dermal fibroblasts (HDF), and its application towards fighting cancer was assessed using melanoma and glioblastoma cancer cells over a duration of 24 and 48 hours. Results: RHA was successfully synthesized  and it demonstrated strong anticancer activity against glioblastoma and melanoma cells at as low as a 1 µg/mL concentration while it did not demonstrate any toxicity against HDF cells. Conclusion: This is the first report on the synthesis of RHA with great potential to be used as a new anticancer agent.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Óleo de Rícino/química , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Catálise , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Hexanos/química , Humanos , Hidroxilamina/química , Lipase/química , Lipase/metabolismo , Melanoma/tratamento farmacológico , Melanoma/patologia , Solventes/química
10.
Proc Natl Acad Sci U S A ; 117(20): 11085-11096, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32358191

RESUMO

Glioblastoma (GBM) is the deadliest adult brain cancer, and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 mo over surgery alone, but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype, and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP causes loss of radiation-induced Nanog mRNA expression, and activation of GSK3 with consecutive posttranslational reduction in p-Akt, Sox2, and ß-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that the combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment-resistant, induced GICs (iGICs).


Assuntos
Antagonistas de Dopamina/farmacologia , Glioblastoma/metabolismo , Fenótipo , Receptores Dopaminérgicos/efeitos dos fármacos , Trifluoperazina/farmacologia , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Modelos Animais de Doenças , Antagonistas de Dopamina/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/radioterapia , Glioma/tratamento farmacológico , Glioma/metabolismo , Glioma/patologia , Glioma/radioterapia , Quinase 3 da Glicogênio Sintase/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , RNA Mensageiro/metabolismo , Tolerância a Radiação , Fatores de Transcrição SOXB1 , Trifluoperazina/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina
11.
Arch Biochem Biophys ; 689: 108412, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32445778

RESUMO

BACKGROUND: Glioblastoma (GB) is the most common neoplasm in the brain. Curcumin, as a known polyphenolic compound extracted from turmeric, is a chemotherapy used in some cancer treatments in China. However, the effect of curcumin on the survivability of GB cells remains to be elucidated. METHODS: We performed a CCK8 assay to detect the viability of GB cells following treatments with curcumin and examined the migration and invasion the ability of these cells using the wound-healing and transwell invasion assays. The cell proliferation and apoptotic proteins were detected by Western blot analyses. We utilized a glioblastoma-xenograft mouse model to assess cell proliferation following curcumin treatment. RESULTS: We found that curcumin inhibited the proliferation, migration, and invasion of U251 and U87 GB cells. We detected that curcumin decreased p-AKT and p-mTOR protein expression, and promoted the apoptosis of U251 and U87 GB cells. Further, we found that curcumin promoted the PTEN and p53 expression, as the tumor suppressor genes. In addition, we administered curcumin to nude mice and found that curcumin decreased the tumor volume, caused necrosis of tumor tissue, and significantly enhanced the PTEN and p53 expression in vivo. CONCLUSIONS: These results indicated that curcumin inhibited proliferation by decreasing the p-AKT/p-mTOR pathway and promoted apoptosis by increasing the PTEN and p53 expression. Our study provided the molecular mechanisms by which curcumin inhibited glioblastoma and its targeted interventions.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Curcumina/uso terapêutico , Glioblastoma/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Curcumina/farmacologia , Feminino , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Nus , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
12.
Pharm Res ; 37(5): 90, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32382838

RESUMO

PURPOSE: The blood-brain barrier limits the application of idarubicin in the therapy of glioblastoma multiforme. Biodegradable, intracranial wafers with prolonged release may increase therapy efficiency. METHODS: Blank wafers, wafers containing 5% w/w and 10% w/w of idarubicin were formulated by solution casting from poly(L-lactide-co-glycolide) and poly(glycolide-co-ε-caprolactone). The following methods were used: NMR, GPC, DSC, FTIR, AFM, UV-VIS, and a viability and proliferation assay for idarubicin action (U87MG cell line). RESULTS: Wafers showed a surface with numerous immersions and hills. A lack of interactions between idarubicin and the copolymers was observed. The substance was entrapped in the matrix and released in two phases for all wafers with the appropriate bolus and maintenance dose. The burst effect was observed for all wafers, however, the biggest bolus for poly(L-lactide-co-glycolide) wafers containing 5% w/w of idarubicin was noted. The stable and steady degradation of poly(glycolide-co-ε-caprolactone) wafers containing 5% w/w of idarubicin ensures the most optimal release profile and high inhibition of proliferation. CONCLUSIONS: Copolymer wafers with idarubicin are an interesting proposition with great potential for the local treatment of glioblastoma multiforme. The release rate and dose may be regulated by the amount and kind of wafers for various effects.


Assuntos
Portadores de Fármacos/síntese química , Glioblastoma/tratamento farmacológico , Idarubicina/uso terapêutico , Polímeros/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular , Liberação Controlada de Fármacos , Humanos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Tecnologia Farmacêutica/métodos
13.
Cochrane Database Syst Rev ; 5: CD013238, 2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32395825

RESUMO

BACKGROUND: Glioblastoma is an uncommon but highly aggressive type of brain tumour. Significant gains have been achieved in the molecular understanding and the pathogenesis of glioblastomas, however clinical improvements are difficult to obtain for many reasons. The current standard of care involves maximal safe surgical resection followed by chemoradiation and then adjuvant chemotherapy European Organisation for Research and Treatment of Cancer and the NCIC Clinical Trials Group (EORTC-NCIC) protocol with a median survival of 14.6 months. Successive phase III international randomised controlled studies have failed to significantly demonstrate survival advantage with newer drugs. Epidermal growth factor receptor (EGFR) is observed to be aberrant in 30% to 60% of glioblastomas. The receptor aberrancy is driven by abnormal gene amplification, receptor mutation, or both, in particular the extracellular vIII domain. EGFR abnormalities are common in solid tumours, and the advent of anti-EGFR therapies in non-small cell lung cancer and colorectal adenocarcinomas have greatly improved clinical outcomes. Anti-EGFR therapies have been investigated amongst glioblastomas, however questions remain about its ongoing role in glioblastoma management. This review aimed to report on the available evidence to date and perform a systematic analysis on the risks and benefits of use of anti-EGFR therapies in glioblastomas. OBJECTIVES: To evaluate the efficacy and harms of anti-EGFR therapies for glioblastoma in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, EBM Reviews databases, with supplementary handsearches to identify all available and relevant studies to 20 April 2020. SELECTION CRITERIA: All randomised controlled trials (RCTs) using anti-EGFR therapies in adults with glioblastoma were eligible for inclusion. Anti-EGFR therapies included tyrosine kinase inhibitors, monoclonal antibodies, or vaccines. The comparison included investigational product added to standard of care versus standard of care or placebo, or investigational product against standard of care or placebo. DATA COLLECTION AND ANALYSIS: The authorship team screened the search results and recorded the extracted data for analysis. We used standard Cochrane methodology to performed quantitative meta-analysis if two or more studies had appropriate and available data. Otherwise, we conducted a qualitative and descriptive analysis. We used the GRADE system to rate the certainty of the evidence. The analysis was performed along the two clinical settings: first-line (after surgery) and recurrent disease (after failure of first line treatment). Where information was available, we documented overall survival, progression-free survival, adverse events, and quality of life data from eligible studies. MAIN RESULTS: The combined searches initially identified 912 records (after removal of duplicates), and further screening resulted in 19 records for full consideration. We identified nine eligible studies for inclusion in the review. There were three first-line studies and six recurrent studies. Five studies used tyrosine kinase inhibitors (TKIs); two studies used monoclonal antibodies; and two studies used targeted vaccines. More recent studies presented greater detail in the conduct of their studies and thus had a lower risk of bias. We observed no evidence benefit in overall survival with the use of anti-EGFR therapy in the first-line or recurrent setting (hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.76 to 1.04; 3 RCTs, 1000 participants, moderate-certainty evidence; and HR 0.79, 95% CI 0.51 to 1.21, 4 RCTs, 489 participants, low-certainty evidence, respectively). All the interventions were generally well tolerated with low-certainty evidence for lymphopenia (odds ratio (OR) 0.97, 95% CI 0.19 to 4.81; 4 RCTs, 1146 participants), neutropenia (OR 1.29, 95% CI 0.82 to 2.03; 4 RCTs, 1146 participants), and thrombocytopenia (OR 3.69, 95% CI 0.51 to 26.51; 4 RCTs, 1146 participants). A notable toxicity relates to ABT-414, where significant ocular issues were detected. The addition of anti-EGFR therapy showed no evidence of an increase in progression-free survival (PFS) in the first-line setting (HR 0.94, 95% CI 0.81 to 1.10; 2 RCTs, 894 participants, low-certainty evidence). In the recurrent setting, there was an increase in PFS with the use of anti-EGFR therapy (HR 0.75, 95% CI 0.58 to 0.96, 3 RCTs, 275 participants, low-certainty evidence). The available quality of life assessment data showed that anti-EGFR therapies were neither detrimental or beneficial when compared to standard care (not estimable). AUTHORS' CONCLUSIONS: In summary, there is no evidence of a demonstrable overall survival benefit with the addition of anti-EGFR therapy in first-line and recurrent glioblastomas. Newer drugs that are specially designed for glioblastoma targets may raise the possibility of success in this population, but data are lacking at present. Future studies should be more selective in pursuing people displaying specific EGFR targets.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Glioblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Encefálicas/mortalidade , Vacinas Anticâncer/uso terapêutico , Progressão da Doença , Glioblastoma/mortalidade , Humanos , Linfopenia/etiologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Neutropenia/etiologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto , Trombocitopenia/etiologia
14.
PLoS One ; 15(5): e0233617, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469935

RESUMO

OBJECTIVES: The aim of the study was to investigate therapeutic efficacy of single- or two-fraction radiotherapy in conjunction with IDO1-inhibition in a syngeneic rat glioblastoma model. IDO is known to cause immunosuppression through breakdown of tryptophan in the tumor microenvironment. METHODS: Gene expression analyses of IDO in glioblastoma were performed with data from publicly available datasets. Fractionation studies were done on animals to evaluate tumor size, immune cell infiltration of tumors and serum profile on day 18 after tumor inoculation. Survival analyses were done with animals carrying intracranial glioblastomas comparing two-fraction radiotherapy+IDO1-inhibition to controls. IDO inhibition was achieved by administration of 1-methyl tryptophan (1-MT), and radiotherapy (RT) was delivered in doses of 8Gy. RESULTS: The expression of IDO1 was increased on gene level in glioblastoma stem cells. Tumor size was significantly reduced in animals treated with 1-MT+RTx 2 (both long and short intervals, i.e. 7 and 4 days between the treatments) as compared to control animals, animals treated with only 1-MT or animals treated with 1-MT+RTx1. Serum levels of IL-1A were significantly altered in all treated animals as compared to control animals. Survival was significantly increased in the animals treated with 1-MT+RTx2 (7-day interval) compared to control animals. CONCLUSIONS: Addition of two-fraction RT to IDO1 inhibition with 1-MT significantly reduced tumor size in animals with glioblastoma. Survival was significantly increased in animals treated with two-fractioned RT+1-MT as compared to untreated controls increased significantly. ADVANCES IN KNOWLEDGE: The currently used combination of only two fractions of radiotherapy and immune therapy is a promising area of research, increasing efficacy compared to single fraction irradiation, while potentially lowering radiation side effects compared to radiation in current clinical practice.


Assuntos
Neoplasias Encefálicas/radioterapia , Inibidores Enzimáticos/uso terapêutico , Glioblastoma/radioterapia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Triptofano/análogos & derivados , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Expressão Gênica , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Ratos , Ratos Endogâmicos F344 , Triptofano/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos
15.
Medicine (Baltimore) ; 99(19): e20011, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384458

RESUMO

BACKGROUND: Glioblastoma is the most common malignant primary brain tumor which has highly expressed vascular endothelial growth factor. To date, various antiangiogenic drugs have been investigated in clinical trials but with no overall conclusion, especially for newly diagnosed glioblastoma (nGBM). In this study, Bayesian network meta-analysis will be used to conduct a comprehensive analysis of the results of different clinical trials, and assess the efficacy of different antiangiogenic drugs on nGBM. METHODS: In order to find more comprehensive information about the application of antiangiogenic drugs in nGBM patients, we searched the MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials for relevant randomized controlled trials. We also reviewed their reference lists to avoid omissions. Cochrane risk of bias tool (V.1.4.3) and Stata (V.15.0) will be used to assess the methodological quality of this review. RESULTS: This study will provide reliable evidence for different antiangiogenic therapies in nGBM patients. CONCLUSION: We will evaluate the relative effectiveness of different antiangiogenic drugs and rank each intervention in nGBM patients through prognosis to provide decision-making reference on which method to choose for clinicians. PROTOCOL REGISTRATION NUMBER: CRD42019146537.


Assuntos
Inibidores da Angiogênese , Glioblastoma , Inibidores da Angiogênese/classificação , Inibidores da Angiogênese/farmacologia , Protocolos Clínicos , Glioblastoma/diagnóstico , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Humanos , Metanálise em Rede , Seleção de Pacientes , Prognóstico , Revisões Sistemáticas como Assunto , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/análise
16.
Cancer Imaging ; 20(1): 35, 2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398076

RESUMO

BACKGROUND: Anti-angiogenic treatment of glioblastoma (GBM) complicates radiologic monitoring. We evaluated magnetic resonance elastography (MRE) as an imaging tool for monitoring the efficacy of anti-VEGF treatment of GBM. METHODS: Longitudinal studies were performed in an orthotopic GBM xenograft mouse model. Animals treated with B20 anti-VEGF antibody were compared to untreated controls regarding survival (n = 13), classical MRI-contrasts and biomechanics as quantified via MRE (n = 15). Imaging was performed on a 7 T small animal horizontal bore MRI scanner. MRI and MRE parameters were compared to histopathology. RESULTS: Anti-VEGF-treated animals survived longer than untreated controls (p = 0.0011) with progressively increased tumor volume in controls (p = 0.0001). MRE parameters viscoelasticity |G*| and phase angle Y significantly decreased in controls (p = 0.02 for |G*| and p = 0.0071 for Y). This indicates that untreated tumors became softer and more elastic than viscous with progression. Tumor volume in treated animals increased more slowly than in controls, indicating efficacy of the therapy, reaching significance only at the last time point (p = 0.02). Viscoelasticity and phase angle Y tended to decrease throughout therapy, similar as for control animals. However, in treated animals, the decrease in phase angle Y was significantly attenuated and reached statistical significance at the last time point (p = 0.04). Histopathologically, control tumors were larger and more heterogeneous than treated tumors. Vasculature was normalized in treated tumors compared with controls, which showed abnormal vasculature and necrosis. In treated tumors, a higher amount of myelin was observed within the tumor area (p = 0.03), likely due to increased tumor invasion. Stiffness of the contralateral hemisphere was influenced by tumor mass effect and edema. CONCLUSIONS: Anti-angiogenic GBM treatment prolonged animal survival, slowed tumor growth and softening, but did not prevent progression. MRE detected treatment effects on tumor stiffness; the decrease of viscoelasticity and phase angle in GBM was attenuated in treated animals, which might be explained by normalized vasculature and greater myelin preservation within treated tumors. Thus, further investigation of MRE is warranted to understand the potential for MRE in monitoring treatment in GBM patients by complementing existing MRI techniques.


Assuntos
Inibidores da Angiogênese/efeitos adversos , Neoplasias Encefálicas/diagnóstico por imagem , Técnicas de Imagem por Elasticidade/métodos , Glioblastoma/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Inibidores da Angiogênese/uso terapêutico , Animais , Anticorpos/efeitos adversos , Anticorpos/imunologia , Anticorpos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Feminino , Glioblastoma/tratamento farmacológico , Camundongos , Camundongos Nus , Fator A de Crescimento do Endotélio Vascular/imunologia
17.
Cancer Treat Rev ; 87: 102029, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32408220

RESUMO

Glioblastomas are the most common malignant primary intrinsic brain tumors. Their incidence increases with age, and males are more often affected. First-line management includes maximum safe surgical resection followed by involved-field radiotherapy plus concomitant and six cycles of maintenance temozolomide chemotherapy. Standards of care at recurrence are much less well defined. Minorities of patients are offered second surgery or re-irradiation, but data on a positive impact on survival from randomized trials are lacking. The majority of patients who are eligible for salvage therapy receive systemic treatment, mostly with nitrosourea-based regimens or, depending on availability, bevacizumab alone or in various combinations. In clinical trials, lomustine alone has been increasingly used as a control arm, assigning this drug a standard-of-care position in the setting of recurrent glioblastoma. Here we review the activity of lomustine in the treatment of diffuse gliomas of adulthood in various settings. The most compelling data for lomustine stem from three randomized trials when lomustine was combined with procarbazine and vincristine as the PCV regimen in the newly diagnosed setting together with radiotherapy; improved survival with PCV was restricted to patients with isocitrate dehydrogenase-mutant tumors. No other agent with the possible exception of regorafenib has shown superior activity to lomustine in recurrent glioblastoma, but activity is largely restricted to patients with tumors with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Hematological toxicity, notably thrombocytopenia often limits adequate exposure.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Lomustina/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Humanos , Lomustina/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
18.
Cancer Cell ; 37(3): 354-370.e7, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32183951

RESUMO

Immunotherapy has emerged as a powerful new chapter in the fight against cancer. However, it has yet to reach its full potential due in part to the complexity of the cancer immune response. We demonstrate that tumor-targeting EDV nanocells function as an immunotherapeutic by delivering a cytotoxin in conjunction with activation of the immune system. These nanocells polarize M1 macrophages and activate NK cells concurrently producing a Th1 cytokine response resulting in potent antitumor function. Dendritic cell maturation and antigen presentation follows, which generates tumor-specific CD8+ T cells, conferring prolonged tumor remission. The combination of cytotoxin delivery and activation of innate and adaptive antitumor immune responses results in a potent cyto-immunotherapeutic with potential in clinical oncology.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Imunidade Inata/efeitos dos fármacos , Salmonella typhimurium/citologia , Adulto , Idoso , Animais , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Linhagem Celular , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/fisiologia , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Receptores ErbB/administração & dosagem , Receptores ErbB/metabolismo , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Imunoterapia/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanoestruturas/química , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia
19.
J Enzyme Inhib Med Chem ; 35(1): 672-681, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32156166

RESUMO

Glioblastoma multiforme (GBM) is the deadliest and the most common primary malignant brain tumour. The median survival for patients with GBM is around one year due to the nature of glioma cells to diffusely invade that make the complete surgical resection of tumours difficult. Based upon the connexin43 (Cx43) model of glioma migration we have developed a computational framework to evaluate MMP inhibition in materials relevant to GBM. Using the ilomastat Leu-Trp backbone, we have synthesised novel sulphonamides and monitored the performance of these compounds in conditioned media expressing MMP3. From the results discussed herein we demonstrate the performance of sulfonamide based MMPIs included AP-3, AP-6, and AP-7.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Metaloproteinase 3 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Inibidores de Metaloproteinases de Matriz/síntese química , Inibidores de Metaloproteinases de Matriz/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Células Tumorais Cultivadas
20.
Radiology ; 295(2): 397-406, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32154775

RESUMO

Background Amide proton transfer (APT) MRI has the potential to demonstrate antitumor effects by reflecting biologically active tumor portion, providing different information from diffusion-weighted imaging (DWI) or dynamic susceptibility contrast (DSC) imaging. Purpose To evaluate whether a change in APT signal intensity after antiangiogenic treatment is predictive of early treatment response in recurrent glioblastoma. Materials and Methods In this retrospective study, APT MRI, DWI, and DSC imaging were performed in patients with recurrent glioblastoma from July 2015 to April 2019, both before treatment and 4-6 weeks after initiation of bevacizumab (follow-up). Progression was based on pathologic confirmation or clinical-radiologic assessment, and progression patterns were defined as local enhancing or diffuse nonenhancing. Changes in mean and histogram parameters (fifth and 95th percentiles) of APT signal intensity, apparent diffusion coefficient, and normalized cerebral blood volume (CBV) between imaging time points were calculated. Predictors of 12-month progression and progression-free survival (PFS) were determined by using logistic regression and Cox proportional hazard modeling and according to progression type. Results A total of 54 patients were included (median age, 56 years [interquartile range, 49-64 years]; 24 men). Mean APT signal intensity change after bevacizumab treatment indicated a low 12-month progression rate (odds ratio [OR], 0.36; 95% confidence interval [CI]: 0.13, 0.90; P = .04) and longer PFS (hazard ratio: 0.38; 95% CI: 0.20, 0.74; P = .004). High mean normalized CBV at follow-up was associated with a high 12-month progression rate (OR, 20; 95% CI: 2.7, 32; P = .04) and shorter PFS (hazard ratio, 9.4; 95% CI: 2.3, 38; P = .002). Mean APT signal intensity change was a significant predictor of diffuse nonenhancing progression (OR, 0.27; 95% CI: 0.06, 0.85; P = .047), whereas follow-up 95th percentile of the normalized CBV was a predictor of local enhancing progression (OR, 7.1; 95% CI: 2.4, 15; P = .04). Conclusion Early reduction in mean amide proton transfer signal intensity at 4-6 weeks after initiation of antiangiogenic treatment was predictive of a better response at 12 months and longer progression-free survival in patients with recurrent glioblastoma, especially in those with diffuse nonenhancing progression. © RSNA, 2020 Online supplemental material is available for this article.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Imagem de Difusão por Ressonância Magnética , Glioblastoma/diagnóstico por imagem , Glioblastoma/tratamento farmacológico , Angiografia por Ressonância Magnética , Progressão da Doença , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prótons , Reprodutibilidade dos Testes , Estudos Retrospectivos
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