RESUMEN
Cancer is a serious public health concern worldwide, and nervous system (NS) cancers are among the most life-threatening malignancies. Efforts have been devoted to introduce natural anticancer agents with minimal side effects. Apigenin is an edible flavonoid that is abundantly found in many vegetables and fruits. Various pharmaceutical activities, including anti-inflammatory, antioxidative, antimicrobial, and anticancer effects have been reported for apigenin. This review provides insights into the therapeutic effects of apigenin and flavonoids with similar structure on glioblastoma and neuroblastoma. Current evidence indicates that apigenin has the unique ability to cross the blood-brain barrier, and its antioxidative, anti-inflammatory, neurogenic, and neuroprotective effects have made this flavonoid a great option for the treatment of neurodegenerative disorders. Meanwhile, apigenin has low toxicity on normal neuronal cells, while induces cytotoxicity on NS cancer cells via triggering several signal pathways and molecular targets. Anticancer effects of apigenin have been contributed to various mechanisms such as induction of cell cycle arrest and apoptosis, and inhibition of migration, invasion, and angiogenesis. Although apigenin is a promising pharmaceutical agent, its low bioavailability is an important issue that must be solved before introducing to clinic. Recently, nano-delivery of apigenin by liposomes and poly lactic-co-glycolide nanoparticles has greatly improved functionality of this agent. Hence, investigating pharmaceutical effects of apigenin-loaded nanocarriers on NS cancer cell lines and animal models is recommended for future studies.
Asunto(s)
Apigenina , Humanos , Apigenina/farmacología , Apigenina/uso terapéutico , Apigenina/química , Animales , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Productos Biológicos/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/química , Flavonoides/farmacología , Flavonoides/uso terapéutico , Flavonoides/químicaRESUMEN
Nervous system malignancies are characterized by rapid progression and poor survival rates. These clinical observations underscore the need for novel therapeutic insights and pharmacological targets. To this end, here, we identify the orphan nuclear receptor NR5A2/LRH1 as a negative regulator of cancer cell proliferation and promising pharmacological target for nervous system-related tumors. In particular, clinical data from publicly available databases suggest that high expression levels of NR5A2 are associated with favorable prognosis in patients with glioblastoma and neuroblastoma tumors. Consistently, we experimentally show that NR5A2 is sufficient to strongly suppress proliferation of both human and mouse glioblastoma and neuroblastoma cells without inducing apoptosis. Moreover, short hairpin RNA-mediated knockdown of the basal expression levels of NR5A2 in glioblastoma cells promotes their cell cycle progression. The antiproliferative effect of NR5A2 is mediated by the transcriptional induction of negative regulators of the cell cycle, CDKN1A (encoding for p21cip1), CDKN1B (encoding for p27kip1) and Prox1 Interestingly, two well-established agonists of NR5A2, dilauroyl phosphatidylcholine (DLPC) and diundecanoyl phosphatidylcholine, are able to mimic the antiproliferative action of NR5A2 in human glioblastoma cells via the induction of the same critical genes. Most importantly, treatment with DLPC inhibits glioblastoma tumor growth in vivo in heterotopic and orthotopic xenograft mouse models. These data indicate a tumor suppressor role of NR5A2 in the nervous system and render this nuclear receptor a potential pharmacological target for the treatment of nervous tissue-related tumors.
Asunto(s)
Glioblastoma/patología , Neoplasias del Sistema Nervioso/patología , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Ciclo Celular/fisiología , Línea Celular Tumoral , Proliferación Celular , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/mortalidad , Humanos , Estimación de Kaplan-Meier , Ratones SCID , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Neoplasias del Sistema Nervioso/metabolismo , Neoplasias del Sistema Nervioso/mortalidad , Células-Madre Neurales/efectos de los fármacos , Neuroblastoma/metabolismo , Neuroblastoma/patología , Fosfatidilcolinas/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Telomere maintenance plays important roles in genome stability and cell proliferation. Tumor cells acquire replicative immortality by activating a telomere-maintenance mechanism (TMM), either telomerase, a reverse transcriptase, or the alternative lengthening of telomeres (ALT) mechanism. Recent advances in the genetic and molecular characterization of TMM revealed that telomerase activation and ALT define distinct neuroblastoma (NB) subgroups with adverse outcomes, and represent promising therapeutic targets in high-risk neuroblastoma (HRNB), an aggressive childhood solid tumor that accounts for 15% of all pediatric-cancer deaths. Patients with HRNB frequently present with widely metastatic disease, with tumors harboring recurrent genetic aberrations (MYCN amplification, TERT rearrangements, and ATRX mutations), which are mutually exclusive and capable of promoting TMM. This review provides recent insights into our understanding of TMM in NB tumors, and highlights emerging therapeutic strategies as potential treatments for telomerase- and ALT-positive tumors.
Asunto(s)
Genoma Humano , Proteína Proto-Oncogénica N-Myc/genética , Neoplasias del Sistema Nervioso/genética , Neuroblastoma/genética , Telomerasa/genética , Telómero/química , Proteína Nuclear Ligada al Cromosoma X/genética , Antineoplásicos/uso terapéutico , Niño , Regulación Neoplásica de la Expresión Génica , Inestabilidad Genómica , Humanos , Mutación , Proteína Proto-Oncogénica N-Myc/metabolismo , Metástasis de la Neoplasia , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Neoplasias del Sistema Nervioso/mortalidad , Neoplasias del Sistema Nervioso/patología , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/mortalidad , Neuroblastoma/patología , Factores de Riesgo , Transducción de Señal , Análisis de Supervivencia , Telomerasa/metabolismo , Telómero/efectos de los fármacos , Telómero/patología , Homeostasis del Telómero , Proteína Nuclear Ligada al Cromosoma X/metabolismoRESUMEN
Neuroblastoma is a pediatric cancer, onset with localized as well as metastatic disease. Localized tumors usually show a high content of aneuploid cells. It is suggested that aneuploid cells with numerical copy number variation (CNV) are generated by chromosome instability (CIN). Patients with a localized tumor respond well to the therapy and show a good outcome. On the contrary, patients with a metastatic tumor have worse outcomes and the cells with structural CNV show high levels of CIN. It is proposed that a favorable outcome in patients with localized disease is associated to the grade of CIN.
Asunto(s)
Aneuploidia , Genoma Humano , Neoplasias del Sistema Nervioso/genética , Neuroblastoma/genética , Factores Protectores , Antineoplásicos/uso terapéutico , Inestabilidad Cromosómica , Variaciones en el Número de Copia de ADN , Humanos , Lactante , Metástasis de la Neoplasia , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Neoplasias del Sistema Nervioso/mortalidad , Neoplasias del Sistema Nervioso/patología , Cresta Neural/metabolismo , Cresta Neural/patología , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/mortalidad , Neuroblastoma/patología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: The current study compared the standard response assessment in neuro-oncology (RANO), immunotherapy RANO (iRANO), and modified RANO (mRANO) criteria as well as quantified the association between progression-free (PFS) and overall survival (OS) in an immunotherapy trial in recurrent glioblastoma (rGBM). PATIENTS AND METHODS: A total of 47 patients with rGBM were enrolled in a prospective phase II convection-enhanced delivery of an IL4R-targeted immunotoxin (MDNA55-05, NCT02858895). Bidirectional tumor measurements were created by local sites and centrally by an independent radiologic faculty, then standard RANO, iRANO, and mRANO criteria were applied. RESULTS: A total of 41 of 47 patients (mean age 56 ± 11.7) were evaluable for response. PFS was significantly shorter using standard RANO compared with iRANO (log-rank, P < 0.0001; HR = 0.3) and mRANO (P < 0.0001; HR = 0.3). In patients who died and had confirmed progression on standard RANO, no correlation was observed between PFS and OS (local, P = 0.47; central, P = 0.34). Using iRANO, a weak association was observed between confirmed PFS and OS via local site measurements (P = 0.017), but not central measurements (P = 0.18). A total of 24 of 41 patients (59%) were censored using iRANO and because they lacked confirmation of progression 3 months after initial progression. A strong correlation was observed between mRANO PFS and OS for both local (R2 = 0.66, P < 0.0001) and centrally determined reads (R2 = 0.57, P = 0.0007). CONCLUSIONS: No correlation between radiographic PFS and OS was observed for standard RANO or iRANO, but a correlation was observed between PFS and OS using the mRANO criteria. Also, the iRANO criteria was difficult to implement due to need to confirm progression 3 months after initial progression, censoring more than half the patients.
Asunto(s)
Glioblastoma/terapia , Inmunoterapia/métodos , Inmunotoxinas/farmacología , Subunidad alfa del Receptor de Interleucina-4/antagonistas & inhibidores , Recurrencia Local de Neoplasia/terapia , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Glioblastoma/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Estudios Prospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
For nearly a decade, researchers in the field of pediatric oncology have been using zebrafish as a model for understanding the contributions of genetic alternations to the pathogenesis of neuroblastoma (NB), and exploring the molecular and cellular mechanisms that underlie neuroblastoma initiation and metastasis. In this review, we will enumerate and illustrate the key advantages of using the zebrafish model in NB research, which allows researchers to: monitor tumor development in real-time; robustly manipulate gene expression (either transiently or stably); rapidly evaluate the cooperative interactions of multiple genetic alterations to disease pathogenesis; and provide a highly efficient and low-cost methodology to screen for effective pharmaceutical interventions (both alone and in combination with one another). This review will then list some of the common challenges of using the zebrafish model and provide strategies for overcoming these difficulties. We have also included visual diagram and figures to illustrate the workflow of cancer model development in zebrafish and provide a summary comparison of commonly used animal models in cancer research, as well as key findings of cooperative contributions between MYCN and diverse singling pathways in NB pathogenesis.
Asunto(s)
Proteínas de Neoplasias/genética , Neoplasias del Sistema Nervioso/genética , Neuroblastoma/genética , Proteínas Proto-Oncogénicas/genética , Proteínas de Pez Cebra/genética , Pez Cebra/genética , Animales , Animales Modificados Genéticamente , Antineoplásicos/farmacología , Modelos Animales de Enfermedad , Edición Génica/métodos , Regulación Neoplásica de la Expresión Génica , Ensayos Analíticos de Alto Rendimiento , Humanos , Mutación , Metástasis de la Neoplasia , Proteínas de Neoplasias/metabolismo , Trasplante de Neoplasias/métodos , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Neoplasias del Sistema Nervioso/metabolismo , Neoplasias del Sistema Nervioso/patología , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/metabolismo , Neuroblastoma/patología , Proteínas Proto-Oncogénicas/metabolismo , Transducción de Señal , Pez Cebra/metabolismo , Proteínas de Pez Cebra/metabolismoRESUMEN
Curcumin, a natural polyphenolic compound derived from the South Asian turmeric plant (Curcuma longa), has well-characterized antioxidant, anti-inflammatory, anti-protein-aggregate, and anticancer properties. Neuroblastoma (NB) is a cancer of the nervous system that arises primarily in pediatric patients. In order to reduce the multiple disadvantages and side effects of conventional oncologic modalities and to potentially overcome cancer drug resistance, natural substances such as curcumin are examined as complementary and supportive therapies against NB. In NB cell lines, curcumin by itself promotes apoptosis and cell cycle arrest through the suppression of serine-threonine kinase Akt and nuclear factor kappa of activated B-cells (NF-κB) signaling, induction of mitochondrial dysfunction, and upregulation of p53 and caspase signaling. While curcumin demonstrates anti-NB efficacy in vitro, cross-validation between NB cell types is currently lacking for many of its specific mechanistic activities. Furthermore, curcumin's low bioavailability by oral administration, poor absorption, and relative insolubility in water pose challenges to its clinical introduction. Numerous curcumin formulations, including nanoparticles, nanocarriers, and microemulsions, have been developed, with these having some success in the treatment of NB. In the future, standardization and further basic and preclinical trials will be required to ensure the safety of curcumin formulations. While the administration of curcumin is clinically safe even at high doses, clinical trials are necessary to substantiate the practical efficacy of curcumin in the prevention and treatment of NB.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Curcumina/farmacología , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Neuroblastoma/tratamiento farmacológico , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Niño , Curcuma/química , Curcumina/química , Curcumina/aislamiento & purificación , HumanosRESUMEN
OPINION STATEMENT: Though the majority of nervous system tumors are sporadic, several clinically relevant genetic syndromes are associated with a predisposition to tumors of the central and peripheral nervous system including neurofibromatosis type 1 (NF1), type 2 (NF2), and schwannomatosis (SWN). These represent prototypical tumor suppressor syndromes where loss of a tumor suppressor gene-protein impairs the cell's ability to regulate cell proliferation. While clinical manifestations vary widely for each of these syndromes, tumors arising in the peripheral nerve sheath are a unifying feature. Clinical clues should prompt the clinician to recognize the underlying genetic syndrome and screen for associated tumors including, among others, plexiform neurofibromas and gliomas in NF1 and vestibular schwannomas, meningiomas, and spinal ependymomas in NF2. Improvements in mechanistic understanding of how the genetic mutations that underlie these syndromes contribute to tumor formation have led to new advances in targeted therapies. MEK inhibitors have shown promise for treating progressive plexiform neurofibromas in NF1. Bevacizumab has been shown to improve hearing and treat vestibular schwannomas in NF2. This article reviews the currently available data on management of tumors associated with these three syndromes.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Neurilemoma/tratamiento farmacológico , Neurofibromatosis/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Humanos , Neoplasias del Sistema Nervioso/complicaciones , Neurilemoma/complicaciones , Neurofibromatosis/complicaciones , Pronóstico , Neoplasias Cutáneas/complicacionesRESUMEN
Long non-coding RNAs (lncRNAs) constitute one of the most broad and diverse classes of cellular transcripts, playing key roles as regulatory molecules in many biological processes. Although the biology of lncRNAs is a new and emerging field of research, several studies have already shown that alterations in the expression of lncRNAs are associated with the development and progression of cancer in different organs and tissues, including central and peripheral nervous system. In this review, we summarize the oncogenic and tumor suppressive roles of lncRNAs in malignant tumors of the nervous system, such as glioma and neuroblastoma, focusing on their functional interactions with DNA, other RNA and protein molecules. We further discuss the potential use of lncRNAs as biomarkers for diagnosis, prognosis and tumor treatment. Gaining insight into the functional association between nervous system malignancies and lncRNAs could offer new perspectives to the development of promising therapeutic tools against cancer.
Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Neoplasias del Sistema Nervioso/diagnóstico , Neoplasias del Sistema Nervioso/tratamiento farmacológico , ARN Largo no Codificante/antagonistas & inhibidores , ARN Largo no Codificante/genética , Animales , Antineoplásicos/química , Humanos , Neoplasias del Sistema Nervioso/genéticaRESUMEN
Pneumocystis jirovecii pneumonia is a life-threatening opportunistic infection in children receiving immunosuppressive chemotherapy. Without prophylaxis, up to 25% of pediatric oncology patients receiving chemotherapy will develop Pneumocystis jirovecii pneumonia. Trimethoprim-sulfamethoxazole is the preferred agent for prophylaxis against Pneumocystis jirovecii pneumonia. Pentamidine may be an acceptable alternative for pediatric patients unable to tolerate trimethoprim-sulfamethoxazole. A retrospective review was conducted of pediatric oncology patients who received ≥1 dose of pentamidine for Pneumocystis jirovecii pneumonia prophylaxis between January 2007 and August 2014. Electronic medical records were reviewed to determine the incidence of breakthrough Pneumocystis jirovecii pneumonia or discontinuation of pentamidine associated with adverse events. A total of 754 patients received pentamidine prophylaxis during the period. There were no cases of probable or proven Pneumocystis pneumonia, and 4 cases (0.5%) of possible Pneumocystis pneumonia. The incidence of possible breakthrough Pneumocystis pneumonia was not significantly different between subgroups based on age (<12 months [1.7%] versus ≥12 months [0.4%], P = 0.3), route of administration (aerosolized [0%] versus intravenous [1.0%], P = 0.2), or hematopoietic stem cell transplant status (transplant [0.4%] versus no transplant [0.8%], P = 0.6). Pentamidine was discontinued due to an adverse drug event in 23 children (3.1%), more frequently for aerosolized than for intravenous administration (7.6% versus 2.2%, respectively, P = 0.004). Intravenous or inhaled pentamidine may be a safe and effective second-line alternative for prophylaxis against Pneumocystis jirovecii pneumonia in children with cancer receiving immunosuppressive chemotherapy or hematopoietic stem cell transplantation.
Asunto(s)
Antifúngicos/administración & dosificación , Neoplasias Hematológicas/inmunología , Huésped Inmunocomprometido , Inmunosupresores/efectos adversos , Neoplasias del Sistema Nervioso/inmunología , Pentamidina/administración & dosificación , Neumonía por Pneumocystis/prevención & control , Administración Intravenosa , Aerosoles , Antifúngicos/efectos adversos , Preescolar , Femenino , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/patología , Trasplante de Células Madre Hematopoyéticas , Humanos , Inmunosupresores/administración & dosificación , Lactante , Recién Nacido , Masculino , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Neoplasias del Sistema Nervioso/patología , Pentamidina/efectos adversos , Pneumocystis carinii/efectos de los fármacos , Pneumocystis carinii/crecimiento & desarrollo , Neumonía por Pneumocystis/microbiología , Estudios Retrospectivos , Combinación Trimetoprim y Sulfametoxazol/administración & dosificaciónRESUMEN
Objectives Neuroblastoma (NB) is the most common pediatric solid tumor derived from the sympathetic nervous system. MYCN is amplified in nearly half of patients with NB, and its association with rapid disease progression and poor outcome is controversial. Characterization of cancer stem cells (CSCs) in NBs has been rarely studied. This study was performed to determine whether MYCN and CD133+ CSCs are associated with chemotherapy resistance and the survival time of patients with NB. Methods Fifty patients with an unequivocal pathological diagnosis of NB were recruited. MYCN expression levels were measured before therapy. CSCs were derived and their multipotency tested by directed differentiation. The patients' responses to chemotherapy and average survival time were compared among the groups as follows: CD133+, CD133-, MYCN amplification ≥5 times (i.e. MYCN≥5), MYCN<5, CD133+ plus MYCN≥5, and CD133- plus MYCN<5. Results CD133+ CSCs differentiated into neuron-like cells. CD133+ patients had a significantly poorer response to chemotherapy than did CD133- patients. CD133+ plus MYCN≥5 patients had a significantly shorter average survival time than did CD133- plus MYCN<5 patients. Conclusions CD133+ CSCs are chemoresistance. CD133 expression and MYCN amplification can be used together as a prognostic indicator of disease outcome.
Asunto(s)
Antígeno AC133/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Regulación Neoplásica de la Expresión Génica , Proteína Proto-Oncogénica N-Myc/genética , Neoplasias del Sistema Nervioso/genética , Neuroblastoma/genética , Antineoplásicos/uso terapéutico , Diferenciación Celular , Niño , Preescolar , Resistencia a Antineoplásicos , Femenino , Dosificación de Gen , Humanos , Lactante , Masculino , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neoplasias del Sistema Nervioso/diagnóstico , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Neoplasias del Sistema Nervioso/mortalidad , Neuroblastoma/diagnóstico , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/mortalidad , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Pronóstico , Análisis de Supervivencia , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/metabolismo , Sistema Nervioso Simpático/patologíaRESUMEN
BACKGROUND: Leptomeningeal carcinomatosis is a rare type of metastatic tumors of the central nervous system. In recent years, with the improvement of neoplasms therapies and longer survival of patients by better systemic control, incidence of leptomeningeal metastases has increased every year. However, there is still lack of effective therapies. The aim of this study is to investigate the efficacy, security and prognosis of intrathecal chemotherapy with methotrexate (MTX) in the treatment of neoplastic meningitis. METHODS: A total of 27 patients were enrolled. We investigated clinical features and cerebrospinal fluid (CSF) examination results retrospectively, and analyzed the adverse reactions as well as prognosis after intrathecal chemotherapy. RESULTS: All 27 patients were treated by intrathecal MTX, 70.4% had clinical remission, however, there was no significant difference in CSF pressure and CSF biochemical changes. We observed that 55.6% patients were all appropriate, 25.9% appeared lower limb numbness and mild pain, no serious irreversible adverse reactions occurred. Median overall survival was 4 months. CONCLUSIONS: We suggest that intrathecal administration of MTX is associated with improvement of symptoms of leptomeningeal metastasis patients and no severe adverse events observed.
Asunto(s)
Carcinomatosis Meníngea/tratamiento farmacológico , Metotrexato/administración & dosificación , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Adulto , Anciano , Femenino , Humanos , Inyecciones Espinales , Neoplasias Pulmonares/patología , Masculino , Carcinomatosis Meníngea/secundario , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias del Sistema Nervioso/secundario , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
We aimed at investigating the distribution and risk of second primary cancers (SPCs) in multiple myeloma (MM) survivors in Germany and Sweden to provide etiological understanding of SPCs and insight into their incidence rates and recording practices. MM patients diagnosed in 1997-2010 at age ≥15 years were selected from the Swedish (nationwide) and 12 German cancer registries. Standardized incidence ratios (SIRs) were used to assess risk of a specific SPC compared to risk of the same first cancer in the corresponding background population. Among 18,735 survivors of first MM in Germany and 7,560 in Sweden, overall 752 and 349 SPCs were recorded, respectively. Significantly elevated SIRs of specific SPCs were observed for acute myeloid leukemia (AML; SIR = 4.9) in Germany and for kidney cancer (2.3), AML (2.3) and nervous system cancer (1.9) in Sweden. Elevated risk for AML was more pronounced in the earlier diagnosis period compared to the later, i.e., 9.7 (4.2-19) for 1997-2003 period versus 3.5 (1.5-6.9) for 2004-2010 in Germany; 3.8 (1.4-8.3) for 1997-2003 versus 2.2 (0.3-7.8) for 2004-2010 in Sweden. We found elevated risk for AML for overall, early diagnosis periods and longer follow-up times in both populations, suggesting possible side effects of treatment for MM patients.
Asunto(s)
Neoplasias Renales/diagnóstico , Leucemia Mieloide Aguda/diagnóstico , Mieloma Múltiple/diagnóstico , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias del Sistema Nervioso/diagnóstico , Sistema de Registros , Adolescente , Adulto , Anciano , Antineoplásicos/uso terapéutico , Diagnóstico Precoz , Femenino , Alemania , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Primarias Secundarias/patología , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Neoplasias del Sistema Nervioso/patología , Factores de Riesgo , Sobrevivientes/estadística & datos numéricos , Suecia , Factores de TiempoAsunto(s)
Antineoplásicos/farmacología , Carbazoles/farmacología , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas del Grupo de Alta Movilidad/antagonistas & inhibidores , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Neoplasias del Sistema Nervioso/metabolismo , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Factores de Elongación Transcripcional/antagonistas & inhibidores , HumanosRESUMEN
Amplification of the MYCN oncogene predicts treatment resistance in childhood neuroblastoma. We used a MYC target gene signature that predicts poor neuroblastoma prognosis to identify the histone chaperone FACT (facilitates chromatin transcription) as a crucial mediator of the MYC signal and a therapeutic target in the disease. FACT and MYCN expression created a forward feedback loop in neuroblastoma cells that was essential for maintaining mutual high expression. FACT inhibition by the small-molecule curaxin compound CBL0137 markedly reduced tumor initiation and progression in vivo. CBL0137 exhibited strong synergy with standard chemotherapy by blocking repair of DNA damage caused by genotoxic drugs, thus creating a synthetic lethal environment in MYCN-amplified neuroblastoma cells and suggesting a treatment strategy for MYCN-driven neuroblastoma.
Asunto(s)
Antineoplásicos/farmacología , Carbazoles/farmacología , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas del Grupo de Alta Movilidad/antagonistas & inhibidores , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Neoplasias del Sistema Nervioso/metabolismo , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Factores de Elongación Transcripcional/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Carbazoles/uso terapéutico , Reparación del ADN/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Proteínas del Grupo de Alta Movilidad/metabolismo , Humanos , Terapia Molecular Dirigida , Transducción de Señal/efectos de los fármacos , Factores de Elongación Transcripcional/metabolismoRESUMEN
OBJECTIVES: The objective of the study is to conduct a systematic review to compare the effects of high-dose chemotherapy (HDCT) with autologous haematopoietic stem cell transplantation (HSCT) versus standard-dose chemotherapy (SDCT) in children with malignant central nervous system (CNS) tumours. METHODS: Standard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction. Ten electronic databases will be searched, along with citation searching and reference checking. Studies assessing the effects of HDCT with HSCT in children with CNS tumours will be included. The outcomes are survival (overall, progression-free, event-free, disease-free), response rates, short- and long-term adverse events and health-related quality of life (HRQoL). Two reviewers will independently screen and select randomised and non-randomised controlled trials and controlled and uncontrolled observational studies for inclusion. Quality assessment will be tailored to the different study designs. Where possible data will be summarised using combined estimates of effect for the hazard ratio for survival outcomes and the risk ratio for response rates. A fixed effect model will be used; sub-group analyses and meta-regression will be used to explore potential sources of heterogeneity between studies. DISCUSSION: Given the poor prognosis of malignant brain tumours in children in terms of survival and quality of life, this review will help guide clinical practice by summarising the current evidence on the use of high-dose myeloblative chemotherapy with stem cell support in children with CNS tumours.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Recurrencia Local de Neoplasia/prevención & control , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Neoplasias del Sistema Nervioso/cirugía , Adolescente , Factores de Edad , Niño , Preescolar , Protocolos Clínicos , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Lactante , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Revisiones Sistemáticas como Asunto , Adulto JovenAsunto(s)
Enfermedades del Sistema Nervioso/tratamiento farmacológico , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Fotoquimioterapia/métodos , Animales , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Modelos Animales de Enfermedad , Humanos , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/patología , Neoplasias del Sistema Nervioso/diagnóstico , Neoplasias del Sistema Nervioso/patología , Neuroglía/efectos de los fármacos , Neuroglía/patología , Neuronas/efectos de los fármacos , Neuronas/patología , Fenómenos Ópticos , Fotoquimioterapia/efectos adversos , Fármacos Fotosensibilizantes/efectos adversos , Fármacos Fotosensibilizantes/uso terapéutico , Accidente Cerebrovascular/etiologíaRESUMEN
Neuroblastoma (NB) is a pediatric tumor of the sympathetic nervous system, which is often associated with elevated catecholamines. More than half of patients with metastatic NB relapse and survival is extremely poor with current therapies. In a high-throughput screen of FDA-approved drugs we identified anti-NB activity for the nonselective ß-adrenergic receptor antagonist propranolol hydrochloride. Propranolol inhibited growth of a panel of fifteen NB cell lines irrespective of MYCN status, and treatment induced apoptosis and decreased proliferation. Activity was dependent on inhibition of the ß2, and not ß1, adrenergic receptor, and treatment resulted in activation of p53 and p73 signaling in vitro. The majority of NB cell lines and primary tumors express ß2 adrenergic receptor and higher mRNA levels correlate with improved patient survival, but expression levels did not correlate with in vitro sensitivity to propranolol. Furthermore, propranolol is synergistic with the topoisomerase I inhibitor SN-38 and propranolol inhibits growth of NB xenografts in vivo at doses similar to those used to treat infants with hemangiomas and hypertension. Taken together, our results suggest that propranolol has activity against NB and thus should be considered in combination treatments for patients with relapsed and refractory NB.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Neuroblastoma/tratamiento farmacológico , Propranolol/farmacología , Animales , Apoptosis/efectos de los fármacos , Enfermedades del Sistema Nervioso Autónomo/tratamiento farmacológico , Enfermedades del Sistema Nervioso Autónomo/metabolismo , Enfermedades del Sistema Nervioso Autónomo/patología , Procesos de Crecimiento Celular/efectos de los fármacos , Proteínas de Unión al ADN , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Neoplasias del Sistema Nervioso/metabolismo , Neoplasias del Sistema Nervioso/patología , Neuroblastoma/metabolismo , Neuroblastoma/patología , Proteínas Nucleares , Receptores Adrenérgicos beta/metabolismo , Proteína Tumoral p73 , Proteínas Supresoras de Tumor , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Retinoids have been studied for the treatment of children with neuroblastoma for >25 years. Posttransplant administration of isotretinoin is standard of care for children with high-risk neuroblastoma, whereas fenretinide remains investigational. Previous preclinical studies have evaluated the interaction of retinoids and cytotoxic agents with conflicting results. We evaluated the schedule-dependent interaction of the cytotoxic agents, vincristine and cisplatin, with the retinoids, isotretinoin and fenretinide, in xenograft models of neuroblastoma. Concomitant administration of isotretinoin or fenretinide with the cytotoxic agents did not result in any clear potentiation of cytotoxicity.