RESUMEN
Toxic metals that are released into aquatic environments from natural and anthropogenic sources are absorbed by aquatic organisms and may threaten the health of both aquatic organisms and humans. Despite this, there have been limited studies on the metal concentrations in fish and humans in Central Asia. This study summarizes the presence of the toxic metals arsenic (As), mercury (Hg), cadmium (Cd), and lead (Pb) in aquatic bodies, fish, and seafood products and conducts a risk assessment. While certain areas show a notable increase in fish and seafood consumption, the overall intake in Central Asia remains below recommended levels. However, in regions with high fish consumption, there is a potential for elevated exposure to toxic metals, especially Hg. The risk of exposure to toxic metals in fish and seafood in Central Asia emerges as a significant concern. Comprehensive monitoring, regulation, and remediation efforts are imperative to ensure the safety of water sources and food consumption in the region. Public awareness campaigns and the establishment of dietary guidelines play a crucial role in minimizing the health risks associated with consumption.
Asunto(s)
Arsénico , Mercurio , Metales Pesados , Animales , Humanos , Alimentos Marinos/análisis , Mercurio/toxicidad , Mercurio/análisis , Metales/toxicidad , Cadmio/toxicidad , Arsénico/toxicidad , Arsénico/análisis , Peces , Asia , Metales Pesados/toxicidad , Metales Pesados/análisis , Medición de Riesgo , Contaminación de Alimentos/análisisRESUMEN
High-risk neuroblastoma is a rapidly growing tumor with a survival rate below 50%. A new treatment strategy is to administer chemotherapeutic drugs metronomically, i.e., at lower doses and frequent intervals. The aim of the study was to investigate the effects of GMX1777, a chemotherapeutic drug affecting cellular energy metabolism, in a mouse model for high-risk neuroblastoma. Female SCID mice were injected s.c. with MYCN-amplified human neuroblastoma cells and randomized to either treatment with GMX1777 or vehicle. In some animals, treatment was discontinued allowing tumor relapse. Treatment response was evaluated using the pediatric preclinical testing program (PPTP). Immunohistochemistry and qRT-PCR was performed on tumor cryosections to investigate the microscopic and molecular changes in tumors in response to GMX1777. Despite an increase in vessel density, tumor regression and a high group response score according to PPTP criteria was induced by GMX1777 without inducing drug resistance. Treatment resulted in inhibition of tumor cell proliferation, vessel maturation, reduced hypoxia, increased infiltration of MHC class II negative macrophages and expansion of the nonvascular stromal compartment. Decreased stromal VEGF-A and PDGF-B mRNA in response to treatment together with the structural data suggest a "deactivation" or "silencing" of the tumor stroma as a paracrine entity. In conclusion, GMX1777 was highly efficient against high-risk neuroblastoma xenografts through modulation of both the tumor cell and stromal compartment.
Asunto(s)
Resistencia a Antineoplásicos , Guanidinas/administración & dosificación , NAD/antagonistas & inhibidores , Neovascularización Patológica , Neuroblastoma/patología , Animales , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Humanos , Immunoblotting , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Proteína Proto-Oncogénica N-Myc , Neuroblastoma/irrigación sanguínea , Proteínas Nucleares/genética , Proteínas Oncogénicas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
AIM: To determine whether concentrations of the angiogenic growth factors hepatocyte growth factor (HGF) and vascular endothelial growth factor A (VEGF-A) correlate with clinical and genetic markers in samples taken at diagnosis in children with neuroblastoma (NB). PATIENTS AND METHODS: Heparin plasma (P-) and serum (S-) samples of healthy controls (n=73, mean age +/- SD 3.5+/-2.1; females/males: 23/50) and patients with NB (n=62; 2.2+/-1.8; 26/36) were collected between 1988 and 1999. Clinical data included age at diagnosis, gender, stage, outcome, amplification of the oncogene MYCN, loss of heterozygosity at the short arm of chromosome 1 (1p LOH) and ploidy. RESULTS: HGF and S-VEGF-A were elevated in NB as compared to controls (38/62 patients, p<0.0001 and p<0.05, Mann-Whitney U test). HGF concentrations were higher in high-stage (stage 3-4) as compared to low-stage (stage 1-2) disease (p<0.01). P-HGF was elevated in patients with 1p LOH (p<0.01), MYCN amplification (p<0.001) and di- or tetraploidy (p<0.001). S-HGF concentration was elevated in patients MYCN-amplified tumors only. Plasma and S-HGF concentrations were higher in the deceased group (p<0.05), but not P or S-VEGF-A. CONCLUSION: This study showed that concentrations of HGF and S-VEGF-A are elevated in patients with NB. Furthermore, HGF and S-VEGF-A concentrations correlate to higher stage disease and HGF correlates to genetic markers known to indicate a poor outcome. These observations imply that HGF and VEGF-A have biological roles in NB and suggest the possibility of interference with HGF or VEGF-A signaling as a therapeutic strategy.
Asunto(s)
Factor de Crecimiento de Hepatocito/sangre , Neuroblastoma/sangre , Neuroblastoma/diagnóstico , Factor A de Crecimiento Endotelial Vascular/sangre , Estudios de Casos y Controles , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Lactante , Recién Nacido , Pérdida de Heterocigocidad , Masculino , Estudios Multicéntricos como Asunto , Proteína Proto-Oncogénica N-Myc , Neuroblastoma/genética , Proteínas Nucleares/genética , Proteínas Oncogénicas/genética , Ploidias , PronósticoRESUMEN
BACKGROUND: High-risk neuroblastoma has an overall five-year survival of less than 40%, indicating a need for new treatment strategies such as angiogenesis inhibition. Recent studies have shown that chemotherapeutic drugs can inhibit angiogenesis if administered in a continuous schedule. The aim of this study was primarily to characterize tumor spread in an orthotopic, metastatic model for aggressive, MYCN-amplified neuroblastoma and secondarily to study the effects of daily administration of the chemotherapeutic agent CHS 828 on tumor angiogenesis, tumor growth, and spread. METHODS: MYCN-amplified human neuroblastoma cells (IMR-32, 2 x 10(6)) were injected into the left adrenal gland in SCID mice through a flank incision. Nine weeks later, a new laparotomy was performed to confirm tumor establishment and to estimate tumor volume. Animals were randomized to either treatment with CHS 828 (20 mg/kg/day; p.o.) or vehicle control. Differences between groups in tumor volume were analyzed by Mann-Whitney U test and in metastatic spread using Fisher's exact test. Differences with p < 0.05 were considered statistically significant. RESULTS: The orthotopic model resembled clinical neuroblastoma in respect to tumor site, growth and spread. Treatment with CHS 828 resulted in tumor regression (p < 0.001) and reduction in viable tumor fraction (p < 0.001) and metastatic spread (p < 0.05) in correlation with reduced plasma levels of the putative tumor marker chromogranin A (p < 0.001). These effects were due to increased tumor cell death and reduced angiogenesis. No treatment-related toxicities were observed. CONCLUSION: The metastatic animal model in this study resembled clinical neuroblastoma and is therefore clinically relevant for examining new treatment strategies for this malignancy. Our results indicate that daily scheduling of CHS 828 may be beneficial in treating patients with high-risk neuroblastoma.
Asunto(s)
Compartimento Celular , Células Endoteliales/patología , Neuroblastoma/patología , Neuroblastoma/terapia , Animales , Autopsia , Calgranulina A/sangre , Compartimento Celular/efectos de los fármacos , Línea Celular Tumoral , Cianuros/toxicidad , Células Endoteliales/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Guanidinas/toxicidad , Humanos , Neoplasias Hepáticas/secundario , Ratones , Ratones SCID , Metástasis de la Neoplasia , Neovascularización Patológica/metabolismo , Neuroblastoma/irrigación sanguínea , Inducción de Remisión , Factores de Riesgo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Zoledronic acid is a new member of the bisphosphonate (BP) class of compounds, a family of closely related synthetic molecules originally derived from the naturally occurring pyrophosphate. These compounds that are potent inhibitors of bone resorption, have been shown to reduce the growth of several cancer cell lines in vitro, and can act as inhibitors of angiogenesis. The angiogenesis inhibitor TNP-470, a synthetic analogue of the fungal antibiotic fumagillin, has been shown to inhibit the growth of multiple tumors in vivo, and is currently in Phase II clinical trials for cancer. MATERIALS AND METHODS: The effects of daily subcutaneous (s.c.) administration of zoledronic acid (0.1 mg/kg) were compared with those of TNP-470 (15 mg/kg/day and 30 mg/kg every other day, s.c.) in a nude mouse xenograft model for the childhood cancer, neuroblastoma (NB). RESULTS: Zoledronic acid reduced the tumor growth by 33% whereas TNP-470 was less effective and reduced the tumor growth by 26% and 11% for animals treated with 15 mg/kg/day and 30 mg/kg every other day, respectively. Analysis of angiogenesis showed a significant reduction of the number of vessels per grid and in vessel length in all the treatment groups. CONCLUSION: Zoledronic acid shows tumoristatic and angiostatic properties that might be beneficial in the treatment of solid tumors such as neuroblastoma.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Difosfonatos/farmacología , Imidazoles/farmacología , Neuroblastoma/irrigación sanguínea , Neuroblastoma/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Ciclohexanos/farmacología , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Femenino , Humanos , Masculino , Ratones , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Neuroblastoma/patología , O-(Cloroacetilcarbamoil) Fumagilol , Sesquiterpenos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Ácido ZoledrónicoRESUMEN
BACKGROUND: The antiepileptic drugs (AEDs) phenytoin, phenobarbital, dimethadione, and carbamazepine cause a similar pattern of malformations in humans, with an increased risk after polytherapy. The teratogenicity has been linked to cardiac rhythm disturbances and hypoxic damage as a consequence of their common potential to inhibit a specific potassium ion current (IKr). The IKr is of major importance for embryonic cardiac repolarization and rhythm regulation. This study investigated whether these AEDs cause irregular rhythm and if various combinations of AEDs result in higher arrhythmia risk than exposure to a single AED. METHODS: The effects on heart rhythm of a single AED (monotherapy), and of various combinations (polytherapy) of AEDs, in gestational day 10 C57BL mouse embryos in culture were analyzed and graphically illustrated during a 25 s recording with a digitalization technique. RESULTS: All of the studied AEDs caused increased intervals between heartbeats (resulting in bradycardia) and large variations in the interval between heartbeats (resulting in irregular rhythm) in a concentration-dependent manner in cultured mouse embryos. Dimethadione caused irregular rhythm at concentrations within and phenytoin slightly above the therapeutic ranges. Polytherapy resulted in more substantial prolongation of the mean interval between heartbeats (>60 ms) than monotherapy at clinically relevant concentrations. CONCLUSIONS: The results suggest that polytherapy more than monotherapy causes substantial prolongation of the cardiac repolarization, a marker associated with high risk of developing irregular rhythm during longer exposure periods (days to months). This supports the idea that the increased risk for malformations following polytherapy is linked to an increased risk for cardiac rhythm disturbances.
Asunto(s)
Anticonvulsivantes/toxicidad , Bradicardia/inducido químicamente , Embrión de Mamíferos/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Corazón/efectos de los fármacos , Bloqueadores de los Canales de Potasio/toxicidad , Animales , Bradicardia/embriología , Dimetadiona/toxicidad , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Técnicas de Cultivo de Embriones , Embrión de Mamíferos/fisiopatología , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Femenino , Edad Gestacional , Corazón/embriología , Ratones , Ratones Endogámicos C57BL , Fenitoína/toxicidad , EmbarazoRESUMEN
BACKGROUND: High risk neuroblastoma (NB) patients have an overall five-year survival of approximately 50%, indicating the need for new treatment strategies, such as angiogenesis inhibition. MATERIALS AND METHODS: The angiogenesis inhibitor TNP-470 (30 mg/kg, every other day, subcutaneously) was given to nude mice with subcutaneous human neuroblastoma xenografts. The plasma concentrations of the angiogenesis stimulators, i.e. vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2) and hepatocyte growth factor (HGF), were assayed longitudinally. Angiogenesis, proliferation and apoptosis were quantified on tumor tissue slides. RESULTS: Upon treatment with TNP-470, angiogenesis was significantly inhibited by the reduction of length and surface area of vessels per tumor volume, without having significant effect on tumor growth, tumor cell proliferation or apoptosis. Plasma concentrations of VEGF-A per tumor volume were significantly increased upon treatment. CONCLUSION: Angiogenesis inhibition must reach a threshold before significant tumor cell apoptosis and a reduction of the tumor growth rate occur.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Ciclohexanos/farmacología , Neuroblastoma/irrigación sanguínea , Neuroblastoma/tratamiento farmacológico , Sesquiterpenos/farmacología , Animales , Bovinos , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Desnudos , Neovascularización Patológica/sangre , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Neuroblastoma/sangre , Neuroblastoma/patología , O-(Cloroacetilcarbamoil) Fumagilol , Factor A de Crecimiento Endotelial Vascular/sangre , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Phenytoin is a human and animal teratogen. Accumulating evidence suggests that the teratogenicity is associated with a potential of phenytoin to cause embryonic cardiac arrhythmia and resultant generation of toxic reactive oxygen species via hypoxia-reoxygenation mechanisms. The A/J mouse is more susceptible to phenytoin teratogenicity than other mouse strains. The aim of this study was to investigate whether A/J mice have other antioxidant enzyme activities than C57BL/6J and CD-1 mice. Also, strain differences in phenytoin effects on embryonic heart rate and rhythm were determined. Another objective was to determine whether a spin trapping agent with capacity to capture reactive oxygen species alter the developmental toxicity of phenytoin. Treatment with this agent resulted in a marked decrease in phenytoin teratogenicity, which supports the idea that reactive oxygen species are important mediators for the teratogenic action of phenytoin. The A/J mice embryos were most susceptible to the adverse cardiac effects of phenytoin and had the highest activity of superoxide dismutase and glutathione peroxidase, while the activity of catalase was the same in embryos of the three different strains. The high activities of antioxidant enzymes in the A/J stain indicate that the sensitivity to develop malformations is caused by excessive arrhythmia-related generation of reactive oxygen species rather than impaired antioxidant defense.
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Embrión de Mamíferos/efectos de los fármacos , Fenitoína/farmacología , Especies Reactivas de Oxígeno/metabolismo , Teratógenos/toxicidad , Animales , Antiarrítmicos/toxicidad , Antioxidantes/metabolismo , Embrión de Mamíferos/fisiología , Femenino , Ratones , Ratones Endogámicos A , Ratones Endogámicos C57BL , EmbarazoRESUMEN
Neuroblastoma (NB) is a rapidly growing, well-vascularized childhood cancer that often presents with metastases. The overall five-year survival in NB is approximately 45% despite multimodality treatment, and therefore there is a clinical need for new therapeutic strategies. NB frequently overexpresses the angiogenic factor VEGF (vascular endothelial growth factor). The aim of this study was to investigate the effect of bevacizumab (Avastin, Genentech/Roche), a humanized anti-VEGF-A antibody, on NB growth in three different xenograft models, chosen to resemble high-risk NB. The human NB cell lines SK-N-AS, IMR-32 and SH-SY5Y, which are poorly differentiated and overexpress VEGF-A, were injected s.c. in immunodeficient mice. Bevacizumab was given intraperitoneally twice weekly at 5 mg/kg body weight, starting at a tumor volume of 0.3 mL. Bevacizumab significantly (p < 0.01-0.05) reduced NB growth in vivo without toxicity by causing a 30-63% reduction of angiogenesis, but had no effect on NB cell survival in vitro. Serum concentrations of VEGF-A increased two- to six-fold during bevacizumab therapy which did not result in faster tumor growth compared with control animals. Based on our experimental data we suggest consideration of bevacizumab in treatment of high-risk NB that does not respond to conventional therapy and that overexpresses VEGF.
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Inhibidores de la Angiogénesis/metabolismo , Anticuerpos Monoclonales/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patología , Trasplante Heterólogo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Bevacizumab , Línea Celular Tumoral , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Ratones , Ratones Desnudos , Neovascularización Patológica/tratamiento farmacológico , Neuroblastoma/tratamiento farmacológicoRESUMEN
BACKGROUND: Epidemiological data suggest a more favorable outcome of breast carcinoma in women taking cardiac glycosides. This study investigated whether digoxin could inhibit tumor growth in mice. MATERIALS AND METHODS: Tumor growth experiments were done in mice grafted with the neuroblastoma cell lines SH-SY5Y, Neuro-2a, colonic cancer cells (LS174T) or Lewis lung cancer cells (LLC). Angiogenesis inhibition was investigated in vitro on fibroblast growth factor-2 (FGF-2)-stimulated bovine endothelial cell (BCE) growth and in vivo in the chick chorioallantoic membrane (CAM) assay. RESULTS: SH-SY5Y and Neuro-2a grafts were inhibited by 44% (p=0.008) and 19% (p=0.007), respectively, whereas the colonic cancer xenografts and LLC syngrafts were less responsive. The neuroblastoma specificity was confirmed in vitro. Digoxin also inhibited angiogenesis in the CAM assay and the BCE cell survival in vitro was 50% at 53 ng/ml. CONCLUSION: Our data suggest that digoxin may be a specific neuroblastoma growth inhibitor and an unspecific inhibitor of angiogenesis.
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Digoxina/farmacología , Neuroblastoma/tratamiento farmacológico , Animales , Carcinoma Pulmonar de Lewis/irrigación sanguínea , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Carcinoma Pulmonar de Lewis/patología , Bovinos , Procesos de Crecimiento Celular/efectos de los fármacos , Embrión de Pollo , Membrana Corioalantoides/irrigación sanguínea , Células Endoteliales/efectos de los fármacos , Femenino , Factor 2 de Crecimiento de Fibroblastos/farmacología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Neovascularización Fisiológica/efectos de los fármacos , Neuroblastoma/irrigación sanguínea , Neuroblastoma/patología , Distribución Aleatoria , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The antiepileptic drug phenytoin (PHT) is a human and animal teratogen. The teratogenicity has been linked to PHT-induced embryonic cardiac arrhythmia and hypoxic damage during a period when regulation of embryonic heart rhythm is highly dependent on a specific K(+) ion current (I(Kr)). PHT has been shown to inhibit I(Kr). The aims of this study were to investigate whether teratogenic doses cause embryonic hypoxia during and after the I(Kr) susceptible period and to further characterize PHT effects on embryonic heart rhythm. METHODS: Pregnant C57BL mice were administered the hypoxia marker pimonidazole followed by PHT or saline (controls) on GD 10 or GD 15. The embryos were fixed and sectioned, and the immunostained sections were analyzed with a computer assisted image analysis. Effects of PHT (0-250 microM) on heart rhythm in GD 10 embryos cultured in vitro were videotaped and then analyzed by using a digitalization technique. RESULTS: PHT dose-dependently increased the hypoxia staining (6- and 11-fold after maternal dosing of 100 and 150 mg/kg, respectively) during the period I(Kr) is expressed and functional (GD 10). In contrast, there were no differences between the PHT doses in hypoxia staining, and much less pronounced hypoxia after this period (GD 15). With increasing PHT concentrations, increased length of the interval (bradycardia) and large variations in length between individual heartbeats (arrhythmia) were recorded. CONCLUSIONS: PHT induced bradycardia/arrhythmia and severe embryonic hypoxia during the I(Kr) susceptible period, supporting the idea of an I(Kr)-arrhythmia-hypoxia-related teratogenic mechanism.
Asunto(s)
Anticonvulsivantes/efectos adversos , Proteínas de Transporte de Catión/metabolismo , Corazón/efectos de los fármacos , Fenitoína/efectos adversos , Canales de Potasio con Entrada de Voltaje/metabolismo , Efectos Tardíos de la Exposición Prenatal , Animales , Canales de Potasio Éter-A-Go-Go , Femenino , Corazón/embriología , Hipoxia/metabolismo , Ratones , Ratones Endogámicos C57BL , EmbarazoRESUMEN
PURPOSE: There is evidence that drug-induced embryonic arrhythmia initiates phenytoin (PHT) teratogenicity. The arrhythmia, which links to the potential of PHT to inhibit a specific potassium channel (Ikr), may result in episodes of embryonic ischemia and generation of reactive oxygen species (ROS) at reperfusion. This study sought to determine whether the proposed mechanism might be relevant for the teratogenic antiepileptic drug trimethadione (TMO). METHODS: Effects on embryonic heart rhythm during various stages of organogenesis were examined in CD-1 mice after maternal administration (125-1,000 mg/kg) of dimethadione (DMO), the pharmacologically active metabolite of TMO. Palatal development was examined after administration of a teratogenic dose of DMO and after simultaneous treatment with DMO and a ROS-capturing agent (alpha-phenyl-N-tert-butyl-nitrone; PBN). The Ikr blocking potentials of TMO and DMO were investigated in HERG-transfected cells by using voltage patch-clamping tests. RESULTS: DMO caused stage-specific (gestation days 9-13 only) and dose-dependent embryonic bradycardia and arrhythmia at clinically relevant maternal plasma concentrations (3-11 mM). Hemorrhage in the nasopharyngeal part of the embryonic palate (within 24 h) preceded cleft palate in fetuses at term. Simultaneous treatment with PBN significantly reduced the incidence of DMO-induced cleft palate, from 40 to 13%. Voltage patch-clamping studies showed that particularly DMO (70% inhibition), but also TMO, had Ikr blocking potential at clinically relevant concentrations. CONCLUSIONS: TMO teratogenicity, in the same way as previously shown for PHT, was associated with Ikr-mediated episodes of embryonic cardiac arrhythmia and hypoxia/reoxygenation damage.