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1.
Biol Reprod ; 110(4): 672-683, 2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38263524

RESUMEN

Chemically defined oocyte maturation media supplemented with FGF2, LIF, and IGF-1 (FLI medium) enabled significantly improved oocyte quality in multiple farm animals, yet the molecular mechanisms behind such benefits were poorly defined. Here, we first demonstrated that FLI medium enhanced mouse oocyte quality assessed by blastocyst formation after in vitro fertilization and implantation and fetal development after embryo transfer. We then analyzed the glucose concentrations in the spent media; reactive oxygen species concentrations; mitochondrial membrane potential; spindle morphology in oocytes; and the abundance of transcripts of endothelial growth factor-like factors, cumulus expansion factors, and glucose metabolism-related genes in cumulus cells. We found that FLI medium enabled increased glucose metabolism through glycolysis, pentose phosphate pathway, and hexosamine biosynthetic pathway, as well as more active endothelial growth factor-like factor expressions in cumulus cells, resulting in improved cumulus cell expansion, decreased spindle abnormality, and overall improvement in oocyte quality. In addition, the activities of MAPK1/3, PI3K/AKT, JAK/STAT3, and mTOR signaling pathways in cumulus cells were assessed by the phosphorylation of MAPK1/3, AKT, STAT3, and mTOR downstream target RPS6KB1. We demonstrated that FLI medium promoted activations of all these signaling pathways at multiple different time points during in vitro maturation.


Asunto(s)
Factor 2 de Crecimiento de Fibroblastos , Técnicas de Maduración In Vitro de los Oocitos , Animales , Ratones , Femenino , Técnicas de Maduración In Vitro de los Oocitos/veterinaria , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factores de Crecimiento Endotelial/análisis , Factores de Crecimiento Endotelial/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Oocitos/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Suplementos Dietéticos , Glucosa/farmacología , Glucosa/metabolismo , Células del Cúmulo/metabolismo
2.
Acta Ophthalmol ; 100 Suppl 273: 3-59, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36343937

RESUMEN

Age-related macular degeneration (AMD) is an eye disease, which causes impaired vision that can lead to blindness. The incidence of AMD increases with age. Retinal pigment epithelial (RPE) cells maintain retinal homeostasis and support the functionality of photoreceptors. In the pathogenesis of AMD, the degeneration of the RPE cells precedes photoreceptor cell death. RPE cells are susceptible to oxidative stress, and chronic inflammation involving nucleotide-binding domain, leucine-rich repeat and pyrin domain 3 (NLRP3) inflammasome activation and impaired autophagy are challenges faced by aged RPE cells in AMD. There are two types of AMD, dry (85-90%) and wet (10-15%) disease forms. Choroidal neovascularization is typical for wet AMD, and anti-vascular endothelial growth factor (anti-VEGF) injections are used to prevent the progression of the disease but there is no curative treatment. There is no cure for the dry disease form, but antioxidants have been proposed as a potential treatment option. Ageing is the most important risk factor of AMD, and tobacco smoke is the most important environmental risk factor that can be controlled. Hydroquinone is a cytotoxic, immunotoxic, carcinogenic and pro-oxidative component of tobacco smoke. The aim of this PhD thesis was to study hydroquinone-induced oxidative stress and NLRP3 inflammasome activation in human RPE cells (ARPE-19 cells). An age-related eye disease study (AREDS) formulation (incl. omega-3 fatty acids, vitamin C and E, copper, zinc, lutein and zeaxanthin), which is clinically investigated p.o. dosing combination of dietary supplements for AMD patients, has been evaluated as a possible treatment and restraining option for AMD. Resvega (4.1.1, Table 2) is a similar kind of product to AREDS with added resveratrol, and many of the components incorporated within Resvega can be considered as belonging to the normal antioxidative defence system of the retina. Another aim was to evaluate the effects of Resvega on hydroquinone-induced oxidative stress or NLRP3 inflammasome activation induced by impaired protein clearance. The results of this study reveal that hydroquinone elevated the activity of NADPH oxidase which subsequently mediated the production of reactive oxygen species (ROS) and predisposed RPE cells to degeneration by reducing levels of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). Hydroquinone induced an NLRP3-independent IL-18 release and NLRP3 accumulation inside the IL-1α-primed cells. Resvega treatment reduced the extent of hydroquinone-induced ROS production and NLRP3 inflammasome activation evoked by impaired protein clearance. Thus, Resvega alleviated hydroquinone- and impaired protein clearance-induced stress in human RPE cells, but more studies are needed, for example, to reveal the most optimal route of administration for targeting the cells in the retina, since both oxidative stress and NLRP3 inflammasome activation are important contributors to the development of AMD and represent significant treatment targets.


Asunto(s)
Células Epiteliales , Estrés Oxidativo , Contaminación por Humo de Tabaco , Degeneración Macular Húmeda , Humanos , Antioxidantes/metabolismo , Factores de Crecimiento Endotelial/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Hidroquinonas , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Epitelio Pigmentado de la Retina/citología , Epitelio Pigmentado de la Retina/patología , Contaminación por Humo de Tabaco/efectos adversos , Degeneración Macular Húmeda/metabolismo
3.
Int J Mol Med ; 34(6): 1529-36, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25270395

RESUMEN

The aim of this study was to explore the effects of Astragalus polysaccharides (APS) on the mRNA expression of epidermal growth factor-like domain 7 (EGFL7) in lung tissue in newborn rats with bronchopulmonary dysplasia (BPD). For this purpose, a total of 96 newborn SD rats were randomly divided into 4 groups (n=24): the control group, air room plus APS group, BPD group and the APS group (20 mg/kg/day). Lung tissues were obtained on days 4, 10 and 14 after birth. Morphological changes were observed and the protein and mRNA expression levels of EGFL7, Bax and Bcl-2 were determined. The rats in the BPD group (BPD induced by hyperoxia) presented with an arrest in alveolar and vascular development and low mRNA and protein expression levels of of EGFL7, Bcl-2 and high levels of Bax compared with the rats in the control group. However, lung damage in the APS intervention group was attenuated compared with the BPD group. The protein and mRNA expression levels of EGFL7 and Bcl-2 were also increased and the level of Bax was decreased in the APS intervention group (P<0.01) compared with the BPD model group after birth on days 4, 10 and 14. Our data demonstrate that APS reduce airway remodeling and alveolar damage by upregulating the expression of EGFL7 and exert protective effects against BPD in neonatal rats. Thus, APS may have potential for use as a therapeutic strategy for BPD.


Asunto(s)
Planta del Astrágalo/química , Displasia Broncopulmonar/prevención & control , Factores de Crecimiento Endotelial/genética , Expresión Génica/efectos de los fármacos , Pulmón/efectos de los fármacos , Polisacáridos/farmacología , Animales , Animales Recién Nacidos , Western Blotting , Displasia Broncopulmonar/genética , Displasia Broncopulmonar/metabolismo , Factores de Crecimiento Endotelial/metabolismo , Hiperoxia , Inmunohistoquímica , Pulmón/metabolismo , Pulmón/patología , Fitoterapia , Preparaciones de Plantas/química , Preparaciones de Plantas/farmacología , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Sustancias Protectoras/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Regulación hacia Arriba/efectos de los fármacos , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo
4.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 23(10): 753-6, 2003 Oct.
Artículo en Chino | MEDLINE | ID: mdl-14626189

RESUMEN

OBJECTIVE: To study the effects of Astragalus membranaceus (AM), Angelica sinensis (AS) and their combination on human umbilical vein endothelial cell (HUVEC) proliferation and cells cycle. METHODS: The effects were observed and studied by means of taking the cultured HUVECs as model to determine the cell proliferation with MTT method, cell cycle was analyzed with cytometry, and vascular endothelial growth factor (VEGF) expression with SABC method. The regulatory effects of AM, AS and their combination on the HUVEC proliferation promoting were observed and studied. RESULTS: AM and AS, used singly or in combination, could promote the growth of endothelial cells, increase the cell population in S phase, the effects showed more significant when used in combination (P < 0.05 or P < 0.001). Meanwhile, VEGF expression in all the medicated group was up-regulated, but in the PBS control group, it showed only weak expression (P < 0.05 or P < 0.01). CONCLUSION: AM and AS have effect in promoting vascular endothelial cell proliferation and DNA synthesis, and showed synergistic effect when they were used in combination, suggesting that these two Chinese herbs could have certain effect on the genesis and development of neogenetic vascularization in ischemic myocardium.


Asunto(s)
Angelica sinensis , Astragalus propinquus , Medicamentos Herbarios Chinos/farmacología , Células Endoteliales/citología , División Celular/efectos de los fármacos , Células Cultivadas , ADN/biosíntesis , Factores de Crecimiento Endotelial/metabolismo , Humanos , Neovascularización Fisiológica , Venas Umbilicales/citología
5.
J Natl Cancer Inst ; 95(19): 1440-52, 2003 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-14519750

RESUMEN

Results of preclinical studies suggesting that the efficacy of molecular therapies is enhanced when they are combined with radiation have generated a surge of clinical trials combining these modalities. We reviewed the literature to identify the rationale and experimental foundation supporting the use of cyclooxygenase-2 (COX-2) inhibitors with standard radiotherapy regimens in current clinical trials. Radiation affects the ability of cells to divide and proliferate and induces the expression of genes involved in signaling pathways that promote cell survival or trigger cell death. Future advances in radiotherapy will hinge on understanding mechanisms by which radiation-induced transcription of genes governs cell death and survival, the selective control of this process, and the optimal approaches to combining this knowledge with existing therapeutic modalities. COX-2 is expressed in all stages of cancer, and in several cancers its overexpression is associated with poor prognosis. Evidence from clinical and preclinical studies indicates that COX-2-derived prostaglandins participate in carcinogenesis, inflammation, immune response suppression, apoptosis inhibition, angiogenesis, and tumor cell invasion and metastasis. Clinical trial results have demonstrated that selective inhibition of COX-2 can alter the development and the progression of cancer. In animal models, selective inhibition of COX-2 activity is associated with the enhanced radiation sensitivity of tumors without appreciably increasing the effects of radiation on normal tissue, and preclinical evidence suggests that the principal mechanism of radiation potentiation through selective COX-2 inhibition is the direct increase in cellular radiation sensitivity and the direct inhibition of tumor neovascularization. Results of current early-phase studies of non-small-cell lung, esophageal, cervical, and brain cancers will determine whether therapies that combine COX-2 inhibitors and radiation will enter randomized clinical trials.


Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Isoenzimas/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Prostaglandinas/biosíntesis , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Celecoxib , Quimioterapia Adyuvante , Ensayos Clínicos como Asunto , Ciclooxigenasa 2 , Progresión de la Enfermedad , Factores de Crecimiento Endotelial/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Linfocinas/metabolismo , Proteínas de la Membrana , Neoplasias/irrigación sanguínea , Neoplasias/enzimología , Neoplasias/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/radioterapia , Prostaglandina-Endoperóxido Sintasas , Prostaglandinas/genética , Prostaglandinas/efectos de la radiación , Pirazoles , Radioterapia Adyuvante , Sulfonamidas/uso terapéutico , Análisis de Supervivencia , Transcripción Genética/efectos de la radiación , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
6.
J Nutr ; 133(9): 2820-5, 2003 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-12949371

RESUMEN

In rats, an isoenergetic low protein diet (LP) given throughout gestation perturbs the development of the endocrine pancreas by reducing beta-cell mass and islet vascularization at birth. Taurine, an important amino acid during development, has been found to be low in fetal and maternal plasma. When added to a LP diet, taurine normalizes beta-cell mass. Therefore, we investigated the ability of taurine to correct altered islet vascularization. Rats were given 20% [control (C)] or 8% (LP) protein in the diet with or without supplementation with 25 g/L taurine (T) in drinking water (C+T and LP+T) during gestation and lactation. Immunostaining for vascular endothelial growth factor (VEGF) and fetal liver kinase-1 (Flk-1), a VEGF receptor, was performed on fetal and neonatal pancreatic sections. Blood vessel density and blood vessel number were analyzed morphometrically on semi-thin sections. Taurine supplementation restored a normal volume and numerical density of vessels in fetal islets. The number of cells showing immunoreactivity for VEGF and Flk-1 was reduced by 33 and 45%, respectively, in islet cells from LP fetuses. In 1-mo-old pups, VEGF-positive cells remained decreased by nearly 22%. Both VEGF and Flk-1 were restored in pancreatic endocrine cells of fetuses and pups given taurine. The LP diet induced a threefold overexpression of Flk-1 in ductal cells, which contain precursors of beta cells. However, taurine supplementation was without effect. In conclusion, underexpression of VEGF and Flk-1 is associated with the lower fetal islet vascularization induced by the maternal malnutrition. The addition of taurine to the maternal diet prevents such damage and has a potential role in islet vasculogenesis.


Asunto(s)
Dieta con Restricción de Proteínas , Feto/anatomía & histología , Islotes Pancreáticos/embriología , Preñez , Taurina/administración & dosificación , Animales , Vasos Sanguíneos/anatomía & histología , Suplementos Dietéticos , Factores de Crecimiento Endotelial/metabolismo , Femenino , Feto/irrigación sanguínea , Feto/citología , Feto/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Linfocinas/metabolismo , Conductos Pancreáticos/embriología , Embarazo , Ratas , Ratas Wistar , Factor A de Crecimiento Endotelial Vascular , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Factores de Crecimiento Endotelial Vascular
7.
Endocrinology ; 144(10): 4403-9, 2003 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-12960047

RESUMEN

Vasoactive intestinal polypeptide (VIP) content is increased in the hyperplastic pituitaries of estrogen (E)-treated rats, thus suggesting that this neuropeptide could mediate the E effect on lactotrophs. E also decreases pituitary TGF-beta1 content, an autocrine/paracrine inhibitor of lactotroph proliferation, and induces pituitary angiogenesis. To elucidate the role of VIP in this context, lactotroph hyperplasia was induced in female Fisher 344 rats by implanting sc pellets of diethylstilbestrol (DES). Twenty-five days later, the rats were treated with three different increasing doses of a VIP receptor antagonist or the vehicle for 5 d. DES treatment resulted in a marked increase of serum prolactin (PRL), pituitary PRL content, PRL mRNA expression, pituitary weight, and pituitary proliferating cell nuclear antigen. DES treatment also increased pituitary VIP content and VIP mRNA levels, but not in the hypothalamus and cerebral cortex. Simultaneously, DES treatment decreased the pituitary TGF-beta1 content and increased the pituitary content of vascular endothelial growth factor. VIP receptor antagonist partially reverted the effect of DES on serum PRL and pituitary PRL, proliferating cell nuclear antigen, TGF-beta1, and vascular endothelial growth factor contents, as well as on pituitary weight, in a dose-dependent relation. These data suggest that pituitary VIP mediates the effect of E on lactotroph hyperplasia, pituitary TGF-beta1, and angiogenesis.


Asunto(s)
Dietilestilbestrol/farmacología , Adenohipófisis/metabolismo , Adenohipófisis/patología , Hipófisis/metabolismo , Prolactina/metabolismo , Péptido Intestinal Vasoactivo/metabolismo , Animales , Comunicación Autocrina , Corteza Cerebral/metabolismo , Factores de Crecimiento Endotelial/metabolismo , Estrógenos no Esteroides/farmacología , Femenino , Hiperplasia , Hipotálamo/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Linfocinas/metabolismo , Tamaño de los Órganos , Comunicación Paracrina , Hipófisis/anatomía & histología , Adenohipófisis/efectos de los fármacos , Prolactina/sangre , Prolactina/genética , Antígeno Nuclear de Célula en Proliferación/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas F344 , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1 , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
8.
Life Sci ; 73(10): 1299-313, 2003 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-12850245

RESUMEN

Epidemiological and animal studies have indicated that consumption of green tea is associated with a reduced risk of developing certain forms of cancer. However, the inhibitory mechanism of green tea in angiogenesis, an important process in tumor growth, has not been well established. In the present study, green tea extract (GTE) was tested for its ability to inhibit cell viability, cell proliferation, cell cycle dynamics, vascular endothelial growth factor (VEGF) and expression of VEGF receptors fms-like tyrosine kinase (Flt-1) and fetal liver kinase-1/Kinase insert domain containing receptor (Flk-1/KDR) in vitro using human umbilical vein endothelial cells (HUVECs). GTE in culture media did not affect cell viability but significantly reduced cell proliferation dose-dependently and caused a dose-dependent accumulation of cells in the G1 phase. The decrease of the expression of Flt-1 and KDR/Flk-1 in HUVEC by GTE was detected with immunohistochemical and Western blotting methods. These results suggest that GTE may have preventive effects on tumor angiogenesis and metastasis through reduction of expression of VEGF receptors.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Endotelio Vascular/efectos de los fármacos , Neovascularización Patológica/prevención & control , Extractos Vegetales/farmacología , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Té/química , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Factores de Crecimiento Endotelial/metabolismo , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Inhibidores Enzimáticos/farmacología , Fase G1/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Linfocinas/metabolismo , Venas Umbilicales , Factor A de Crecimiento Endotelial Vascular , Receptor 1 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Factores de Crecimiento Endotelial Vascular
9.
Int J Mol Med ; 12(2): 269-73, 2003 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12851730

RESUMEN

Blood supply plays a crucial role in solid tumour development and leukaemogenesis. It has been suggested that blocking of angiogenesis could be possible in cancer therapy. We have demonstrated the antiproliferative activity of Gleditsia sinensis fruit extract (GSE) on various human solid tumour cancer cell lines as well as leukaemia cell lines and primary cultured leukaemia cells obtained from leukaemia patients. However, the antiangiogenic potential of GSE has not been demonstrated. Here we demonstrated that GSE could reduce vascular endothelial growth factor (VEGF) mRNA expression in dose- and time course-dependently in MDA-MB231 breast cancer and HepG2 hepatoblastoma cell lines as measured by reverse transcriptase polymerase chain reaction. Enzyme-linked immunosorbent assay further showed that GSE could reduce the VEGF secretion from various cancer cell lines including MDA-MB231, HepG2, HL-60 (acute promyelocytic leukaemia) and eleven primary cultured leukaemia cells obtained from acute myelogenous leukaemia patients. In vivo chick chorioallantoic membrane assay illustrated that GSE could reduce the angiogenic activity of basic fibroblast growth factor. Taken together, the information suggested that GSE could be potentially used as an angiogenic inhibitor in both solid tumour and leukaemia therapy.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Gleditsia/química , Leucemia Mieloide/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Extractos Vegetales/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Carcinoma Hepatocelular/sangre , Embrión de Pollo , Ensayos de Selección de Medicamentos Antitumorales/métodos , Factores de Crecimiento Endotelial/genética , Factores de Crecimiento Endotelial/metabolismo , Femenino , Factor 2 de Crecimiento de Fibroblastos/efectos de los fármacos , Frutas/química , Células HL-60/efectos de los fármacos , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Leucemia Mieloide/sangre , Neoplasias Hepáticas/sangre , Linfocinas/efectos de los fármacos , Linfocinas/genética , Linfocinas/metabolismo , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Células Tumorales Cultivadas , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
10.
Cancer Res ; 63(8): 1764-8, 2003 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-12702559

RESUMEN

Hypoxia-inducible factor (HIF) plays an important role in determining patterns of gene expression in cancer. HIF is down-regulated in oxygenated cells by a series of Fe (II) and 2-oxoglutarate dependent dioxygenases that hydroxylate specific residues in the regulatory HIF-alpha subunits. Because these enzymes require ascorbate for activity in vitro we analyzed the effects of ascorbate on HIF in human cancer cell lines. Ascorbate at physiological concentrations (25 micro M) strikingly suppressed HIF-1alpha protein levels and HIF transcriptional targets, particularly when the system was oncogenically activated in normoxic cells. Similar results were obtained with iron supplementation. These results indicate that both ascorbate and iron availability have major effects on HIF, and imply that the system is commonly regulated by limiting hydroxylase activity under normoxic tissue culture conditions.


Asunto(s)
Ácido Ascórbico/farmacología , Neoplasias/metabolismo , Factores de Transcripción/biosíntesis , Adenocarcinoma/metabolismo , Neoplasias de la Mama/metabolismo , Hipoxia de la Célula/fisiología , Factores de Crecimiento Endotelial/biosíntesis , Factores de Crecimiento Endotelial/genética , Factores de Crecimiento Endotelial/metabolismo , Femenino , Compuestos Ferrosos/farmacología , Transportador de Glucosa de Tipo 1 , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Linfocinas/biosíntesis , Linfocinas/genética , Linfocinas/metabolismo , Masculino , Proteínas de Transporte de Monosacáridos/biosíntesis , Proteínas de Transporte de Monosacáridos/genética , Neoplasias/genética , Neoplasias Ováricas/metabolismo , Procolágeno-Prolina Dioxigenasa/metabolismo , Neoplasias de la Próstata/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Factores de Transcripción/genética , Activación Transcripcional/efectos de los fármacos , Transferrina/farmacología , Células Tumorales Cultivadas , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
11.
J Immunol ; 170(6): 2993-3001, 2003 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-12626552

RESUMEN

Activation of macrophages leads to the secretion of cytokines and enzymes that shape the inflammatory response and increase metabolic processes. This, in turn, results in increased production of reactive oxygen species. The role of Cu/Zn superoxide dismutase (SOD-1), an important enzyme in cellular oxygen metabolism, was examined in activated peritoneal elicited macrophages (PEM) and in several inflammatory processes in vivo. LPS and TNF-alpha induced SOD-1 in PEM. SOD-1 induction by LPS was mainly via extracellular signal-regulated kinase-1 activation. Transgenic mice overexpressing SOD-1 demonstrated a significant increase in the release of TNF-alpha and of the metalloproteinases MMP-2 and MMP-9 from PEM. Disulfiram (DSF), an inhibitor of SOD-1, strongly inhibited the release of TNF-alpha, vascular endothelial growth factor, and MMP-2 and MMP-9 from cultured activated PEM. These effects were prevented by addition of antioxidants, further indicating involvement of reactive oxygen species. In vivo, transgenic mice overexpressing SOD-1 demonstrated a 4-fold increase in serum TNF-alpha levels and 2-fold stronger delayed-type hypersensitivity reaction as compared with control nontransgenic mice. Conversely, oral administration of DSF lowered TNF-alpha serum level by 4-fold, lowered the delayed-type hypersensitivity response in a dose-dependent manner, and significantly inhibited adjuvant arthritis in Lewis rats. The data suggest an important role for SOD-1 in inflammation, establish DSF as a potential inhibitor of inflammation, and raise the possibility that regulation of SOD-1 activity may be important in the treatment of immune-dependent pathologies.


Asunto(s)
Inflamación/enzimología , Inflamación/inmunología , Superóxido Dismutasa/fisiología , Administración Oral , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/antagonistas & inhibidores , Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/farmacología , Artritis Experimental/prevención & control , Células Cultivadas , Colagenasas/metabolismo , Cobre/farmacología , Disulfiram/administración & dosificación , Disulfiram/antagonistas & inhibidores , Disulfiram/farmacología , Factores de Crecimiento Endotelial/antagonistas & inhibidores , Factores de Crecimiento Endotelial/metabolismo , Activación Enzimática/inmunología , Femenino , Humanos , Hipersensibilidad Tardía/enzimología , Hipersensibilidad Tardía/inmunología , Inflamación/metabolismo , Inflamación/prevención & control , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Lipopolisacáridos/farmacología , Linfocinas/antagonistas & inhibidores , Linfocinas/metabolismo , Activación de Macrófagos/efectos de los fármacos , Activación de Macrófagos/inmunología , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/enzimología , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/fisiología , Ratas , Ratas Endogámicas Lew , Superóxido Dismutasa/biosíntesis , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/fisiología , Regulación hacia Arriba/inmunología , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
12.
J Cereb Blood Flow Metab ; 23(2): 166-80, 2003 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-12571448

RESUMEN

Angiogenesis is an intricately regulated phenomenon. Its mechanisms in the ischemic brain have not been clearly elucidated. The authors investigated expression of angiogenesis-related genes using a complementary DNA (cDNA) array method as well as Western blotting and immunohistochemistry, and compared these studies with a temporal profile of angiogenesis in mouse brains after ischemia. The number of vessels significantly increased 3 days after injury, and proliferating endothelial cells increased as early as 1 day. This means that angiogenesis occurs immediately after the injury. Ninety-six genes implicated in angiogenesis were investigated with a cDNA array study. It was found that 42, 29, and 13 genes were increased at 1 hour, 1 day, and 21 days, respectively. Most of the well-known angiogenic factors increased as early as 1 hour. Vessel-stabilizing factors such as thrombospondins also increased. At 1 day, however, thrombospondins decreased to lower levels than in the control, indicating a shift from vascular protection to angiogenesis. At 21 days, many genes were decreased, but some involved in tissue repair were newly increased. Western blotting and immunohistochemistry showed findings compatible with the cDNA array study. Many molecules act in an orchestrated fashion in the brain after ischemia and should be taken into account for therapeutic angiogenesis for stroke.


Asunto(s)
Isquemia Encefálica/complicaciones , Isquemia Encefálica/genética , Encéfalo/fisiopatología , Neovascularización Patológica/etiología , Inductores de la Angiogénesis/metabolismo , Angiopoyetina 1 , Angiopoyetina 2 , Animales , Vasos Sanguíneos/patología , Encéfalo/patología , Isquemia Encefálica/patología , Isquemia Encefálica/fisiopatología , Circulación Cerebrovascular , ADN Complementario/genética , Factores de Crecimiento Endotelial/metabolismo , Endotelio Vascular/patología , Etiquetado Corte-Fin in Situ , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Linfocinas/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Trombospondina 1/metabolismo , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Factores de Crecimiento Endotelial Vascular
13.
Int J Cancer ; 104(5): 603-10, 2003 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-12594815

RESUMEN

Malignant mesothelioma (MM) is a locally aggressive tumor that originates from the mesothelial cells of the pleural and sometimes peritoneal surface. Conventional treatments for MM, consisting of chemotherapy or surgery give little survival benefit to patients, who generally die within 1 year of diagnosis. Hence, there is an urgent need for the development of alternative therapies. Vascular endothelial growth factor (VEGF) is an autocrine growth factor for MM. The closely related molecule, VEGF-C, is also implicated in malignant mesothelioma growth. VEGF-C and its cognate receptor VEGFR-3 are co-expressed in mesothelioma cell lines. A functional VEGF-C autocrine growth loop was demonstrated in mesothelioma cells by targeting VEGF-C expression and binding to VEGFR-3. The ability of novel agents that reduce the levels of VEGF and VEGF-C to inhibit mesothelioma cell growth in vitro was assessed. Antisense oligonucleotide (ODN) complementary to VEGF that inhibited VEGF and VEGF-C expression simultaneously specifically inhibited mesothelioma cell growth. Similarly, antibodies to VEGF receptor (VEGFR-2) and VEGF-C receptor (VEGFR-3) were synergistic in inhibiting mesothelioma cell growth. In addition, a diphtheria toxin-VEGF fusion protein (DT-VEGF), which is toxic to cells that express VEGF receptors was very effective in inhibiting mesothelioma cell growth in vitro. These results indicate that targeting VEGF and VEGF-C simultaneously may be an effective therapeutic approach for malignant mesothelioma.


Asunto(s)
Antineoplásicos/farmacología , Comunicación Autocrina/efectos de los fármacos , Factores de Crecimiento Endotelial/antagonistas & inhibidores , Factores de Crecimiento Endotelial/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Linfocinas/antagonistas & inhibidores , Linfocinas/metabolismo , Mesotelioma/metabolismo , Mesotelioma/patología , Anticuerpos/farmacología , Anticuerpos/uso terapéutico , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Toxina Diftérica/farmacología , Factores de Crecimiento Endotelial/genética , Factores de Crecimiento Endotelial/farmacología , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/farmacología , Linfocinas/genética , Linfocinas/farmacología , Mitógenos/farmacología , Oligorribonucleótidos Antisentido , Células Tumorales Cultivadas , Factor A de Crecimiento Endotelial Vascular , Factor C de Crecimiento Endotelial Vascular , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptor 3 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 3 de Factores de Crecimiento Endotelial Vascular/metabolismo , Factores de Crecimiento Endotelial Vascular
14.
Clin Cancer Res ; 9(1): 355-62, 2003 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-12538488

RESUMEN

PURPOSE: The availability of noninvasive techniques to detect the effects of antiangiogenic agents is critically important for optimizing treatment of cancer with these agents. Magnetic resonance imaging (MRI) is one such noninvasive technique that is routinely used clinically. EXPERIMENTAL DESIGN: In this study, we have evaluated the use of MRI of the intravascular contrast agent albumin-GdDTPA to detect the effects of the antiangiogenic agent TNP-470 on the vascular volume and permeability of the MatLyLu prostate cancer model. RESULTS: TNP-470-treated tumors demonstrated a significant decrease of vascular volume, as well as a significant reduction in vascular and permeable regions, compared with volume-matched control tumors. Although the fractional volume of permeable regions in the tumor decreased, the average value of tumor permeability did not decrease significantly. This was attributable to increase in permeability in some regions of the tumor. These regions were mostly associated with low vascular volume. ELISA assays of control and treated MatLyLu tumors also detected a significant increase of vascular endothelial growth factor in the TNP-470-treated tumors. CONCLUSION: MRI detected significant changes in tumor vascular characteristics after treatment with TNP-470.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Neoplasias/metabolismo , Sesquiterpenos/farmacología , Animales , Antibióticos Antineoplásicos/farmacología , Medios de Contraste/farmacología , Ciclohexanos , Factores de Crecimiento Endotelial/metabolismo , Ensayo de Inmunoadsorción Enzimática , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Linfocinas/metabolismo , Imagen por Resonancia Magnética , Masculino , Neovascularización Patológica , O-(Cloroacetilcarbamoil) Fumagilol , Neoplasias de la Próstata/metabolismo , Ratas , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
15.
J Natl Cancer Inst ; 94(19): 1484-93, 2002 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-12359857

RESUMEN

BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent angiogenic cytokine, and various inhibitory agents, including specific antibodies, have been developed to block VEGF-stimulated angiogenesis. We developed HuMV833, a humanized version of a mouse monoclonal anti-VEGF antibody (MV833) that has antitumor activity against a number of human tumor xenografts, and investigated the distribution and biologic effects of HuMV833 in patients in a phase I trial. METHODS: Twenty patients with progressive solid tumors were treated with various doses of HuMV833 (0.3, 1, 3, or 10 mg/kg). Positron emission tomography with (124)I-HuMV833 was used to measure the antibody distribution in and clearance from tissues. Magnetic resonance imaging was used to measure the vascular permeability surface area product with a first-pass pharmacokinetic model (k(fp)) to determine tumor vascular permeability. RESULTS: The antibody was generally well tolerated, although the incremental dose, phase I study design, and pharmacodynamic endpoints could not identify the optimum biologically active dose. Antibody distribution and clearance were markedly heterogeneous between and within patients and between and within individual tumors. HuMV833 distribution to normal tissues also varied among patients, but the antibody was cleared from these tissues in a homogeneous fashion. Permeability was strongly heterogeneous between and within patients and between and within individual tumors. All tumors showed a reduction in k(fp) 48 hours after the first treatment (median = 44%; range = 4%-91%). CONCLUSIONS: Because of the heterogeneity in tumor biology with respect to antibody uptake and clearance, we suggest that either intrapatient dose escalation approaches or larger, more precisely defined patient cohorts would be preferable to conventional strategies in the design of phase I studies with antiangiogenic compounds like HuMV833.


Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Factores de Crecimiento Endotelial/inmunología , Linfocinas/inmunología , Imagen por Resonancia Magnética/métodos , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Neovascularización Patológica/fisiopatología , Animales , Anticuerpos Monoclonales Humanizados , Formación de Anticuerpos , Permeabilidad Capilar , Relación Dosis-Respuesta Inmunológica , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Factores de Crecimiento Endotelial/metabolismo , Humanos , Radioisótopos de Yodo , Linfocinas/metabolismo , Macaca fascicularis/inmunología , Dosis Máxima Tolerada , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Neoplasias/irrigación sanguínea , Neoplasias/inmunología , Distribución Tisular , Tomografía Computarizada de Emisión , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
16.
Acta Pharmacol Sin ; 23(10): 919-23, 2002 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-12370096

RESUMEN

AIM: To study the protective effects of Ginkgo biloba extract (GbE) against rat aortic endothelial cells (RAEC) damage induced by lysophosphatidylcholine (LPC). METHODS: Cell injury were determined by MTT assay and LDH release. Vascular endothelial growth factor (VEGF) protein production from RAEC was determined by enzyme-linked immunosorbent assay (ELISA). VEGF mRNA expression was examined by in situ hybridization and dot blot. RESULTS: GbE 0.01-1 microg/L prevented LPC-induced injury in cultured RAEC in a concentration-dependent manner. Cultured RAEC could express VEGF protein and VEGF mRNA was induced by LPC 5 mg/L. GbE could inhibit the expression of VEGF protein and VEGF mRNA in co-cultured RAEC with LPC. CONCLUSION: LPC could induce a strong expression of VEGF in RAEC. GbE could protect RAEC against the LPC-induced damage and downregulate VEGF protein and VEGF mRNA expression in cultured RAEC.


Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Factores de Crecimiento Endotelial/metabolismo , Endotelio Vascular/efectos de los fármacos , Ginkgo biloba/química , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Linfocinas/metabolismo , Animales , Aorta/citología , Aorta/metabolismo , Células Cultivadas , Factores de Crecimiento Endotelial/genética , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Ensayo de Inmunoadsorción Enzimática , Péptidos y Proteínas de Señalización Intercelular/genética , Linfocinas/genética , Lisofosfatidilcolinas , Masculino , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Wistar , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
17.
Med Hypotheses ; 59(3): 344-8, 2002 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-12208167

RESUMEN

Angiogenesis, cellular growth and invasion of a cancer cell are attractive targets for new treatment strategies of malignancies in recent years. The evidences are accumulating that ACE inhibitors and angiotensin II type 1 antagonists could be novel anti-angiogenic, anti-invasive, and even anti-growth agents against neoplastic tissues: The renin-angiotensin system promotes angiogenesis directly or indirectly and growth of neoplastic cell. Some tumors carry angiotensin II type 1 receptors. Angiotensin II antagonists and angiotensin-I-converting enzyme inhibitors have shown some anti-neoplastic actions. Angiotensin II receptor blocker losartan antagonises platelets, which are thought to modulate via vascular endothelial growth factor. They may even protect the patient from the major toxicity of chemotherapy and/or radiotherapy, myelotoxicity, enabling us to give higher doses and end up with higher success rate. We believe that these agents can be useful on clinical grounds and suggest their incorporation into clinical studies.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Antihipertensivos/farmacología , Antineoplásicos/farmacología , Proteínas de Neoplasias/antagonistas & inhibidores , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Antineoplásicos/uso terapéutico , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Carcinoma Pulmonar de Lewis/irrigación sanguínea , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Factores de Crecimiento Endotelial/metabolismo , Hematopoyesis/efectos de los fármacos , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Linfocinas/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz , Ratones , Invasividad Neoplásica , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Oligopéptidos/antagonistas & inhibidores , Activación Plaquetaria/efectos de los fármacos , Receptor de Angiotensina Tipo 1 , Sistema Renina-Angiotensina/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
18.
JPEN J Parenter Enteral Nutr ; 26(5): 285-9, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-12216707

RESUMEN

BACKGROUND: Omega-3 fatty acids, the principal component of fish oil, have been demonstrated to have antiinflammatory properties. The role of eicosapentaenoic acid (EPA) supplementation for cancer patients is currently under investigation; however, the mechanisms of EPA activity have not been defined. The purpose of this study was to characterize tumor-specific and treatment-specific effects of supplemental dietary EPA in an animal model of progressive malignancy. METHODS: Fischer 344 rats (200-250 g) underwent flank implantation of the methycholanthrene (MCA)-induced fibrosarcoma on day 0. Rats were randomly divided into 3 treatment groups on day 13: EPA (1 mL, 5.0 g/kg per day) + 10 IU vitamin E; corn oil (1 mL) + 10 IU vitamin E, and saline (1 mL) + 10 IU vitamin E (vitamin E was used to prevent fatty acid oxidation). On day 14, gavage feeding was started and was continued through day 28. The animals were killed on day 29, and the tumors were removed. The tumors were weighed and divided by the tumor-free carcass weight to obtain percentage of tumor volume, and the livers were flash frozen. Vascular endothelial growth factor-alpha (VEGF-alpha) and cyclo-oxygenase 2 (COX-2) mRNA were measured by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: EPA rats had significant reductions in tumor volume compared with isocaloric corn oil and control saline animals (25%, p < .01 and 33%, p < .01, respectively). Rats receiving EPA demonstrated decreased VEGF-alpha mRNA levels (0.023 +/- 0 0.001) compared with those receiving corn oil (0.129 +/- 0.047) or saline (0.150 +/- 0.026; p < .05). CONCLUSIONS: These data demonstrate that EPA supplementation inhibits tumor growth, potentially through alterations in the expression of the pro-angiogenic VEGF-alpha. The mechanism(s) of EPA as an inhibitor of tumor-related angiogenic growth factors may be associated with COX-2 enzyme fatty acid metabolism and merits further study.


Asunto(s)
Ácido Eicosapentaenoico/administración & dosificación , Factores de Crecimiento Endotelial/metabolismo , Fibrosarcoma/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Linfocinas/metabolismo , Animales , División Celular/efectos de los fármacos , Ciclooxigenasa 2 , Suplementos Dietéticos , Modelos Animales de Enfermedad , Ácido Eicosapentaenoico/farmacología , Factores de Crecimiento Endotelial/genética , Fibrosarcoma/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular/genética , Isoenzimas/genética , Isoenzimas/metabolismo , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Linfocinas/efectos de los fármacos , Linfocinas/genética , Prostaglandina-Endoperóxido Sintasas/genética , Prostaglandina-Endoperóxido Sintasas/metabolismo , ARN Mensajero/análisis , Distribución Aleatoria , Ratas , Ratas Endogámicas F344 , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
19.
Scand J Urol Nephrol ; 36(3): 182-7, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-12201932

RESUMEN

OBJECTIVE: Finasteride has been shown to reduce prostate bleeding in patients with benign prostatic hyperplasia (BPH). The mechanisms behind this are not known, but it has been suggested that finasteride reduces bleeding by inhibiting angiogenesis in the prostate. Studies in animals have shown that castration rapidly induces involution of the prostate vasculature, and androgen-stimulated prostate growth may be angiogenesis dependent. The objective of this study was to explore the response to finasteride on the vasculature and the expression of vascular endothelial growth factor (VEGF), a potent regulatory factor of angiogenesis in human prostate tissue. MATERIAL AND METHODS: Patients with BPH were randomly assigned to 3 months of treatment either with finasteride (5 mg/day) or placebo before undergoing transurethral resection of the prostate (TURP). Prostate tissue VEGF expression was quantified by Western blot and the vascular density determined in Factor VIII immunostained tissue sections. Serum concentrations of VEGF were measured with ELISA technique. RESULTS: Patients treated with finasteride (n = 15) showed a decrease in prostate tissue VEGF(165) expression compared with placebo (n = 13) treated patients (p < 0.05), but the vascular density and the serum VEGF levels were unaffected. CONCLUSIONS: This study shows that finasteride treatment decreases VEGF expression in the human prostate.


Asunto(s)
Inhibidores de 5-alfa-Reductasa , Factores de Crecimiento Endotelial/metabolismo , Inhibidores Enzimáticos/farmacología , Finasterida/farmacología , Linfocinas/metabolismo , Próstata/metabolismo , Hiperplasia Prostática/tratamiento farmacológico , Western Blotting , Finasterida/uso terapéutico , Humanos , Inmunohistoquímica , Masculino , Microcirculación/efectos de los fármacos , Estudios Prospectivos , Próstata/irrigación sanguínea , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/cirugía , Resección Transuretral de la Próstata , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
20.
Am J Clin Oncol ; 25(4): 325-36, 2002 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12151958

RESUMEN

The MX1 xenotransplant growing in nude mice was used as a model for estrogen- and progesterone-receptor-negative breast cancer. The effects of different therapeutic regimens-combinations of hyperthermia, chemotherapy, and irradiation-on the expression of proteins playing a role in tumor vascularization and apoptosis were investigated. Additionally, MX-1 tumors were exposed to hypoxia to investigate changes in protein expression related to angiogenesis. This is of particular importance with respect to antiangiogenic therapies that may be combined with the treatments mentioned before. Endothelial and adhesion factors, extracellular matrix (ECM) factors, apoptosis-regulating factors, and neuronal factors were examined by immunohistochemical techniques. Concerning vascularization, the most prominent changes were seen in the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which increased strongly after hypoxia. The other cytokines, adhesion and ECM molecules, were either little affected or unaffected by the therapy. At the ultrastructural level, the walls of the tumor vessels are of the sinusoidal type, possessing many fenestrations. With regard to the second focus of this investigation, apoptosis, tumor cells again exerted the strongest differences after hypoxia where c-myc was clearly enhanced, whereas the effects on p53, bcl-2, and CD95 were extremely weak or not detectable. Furthermore, the neurotransmitter somatostatin, a possible "external" regulator of apoptosis, did not show treatment-related changes. In summary, it was shown that 1) within the group of apoptosis-regulating proteins c-myc was particularly affected by hypoxia, indicating a possible role for an activation-induced pathway of apoptosis in this context; 2) minor changes seen after treatment combined with hyperthermia point to a more acute vascular reaction (=dilatation), causing an increase of tissue pO2 rather than angiogenesis; and 3) the concentrations of the angiogenic factors VEGF and bFGF rose strongly under hypoxia, thereby possibly exerting counterproductive effects to antiangiogenic therapy but not to thermochemotherapy or irradiation. This supports the concept of a combined antiangiogenic, hyperthermia, chemo- and irradiation therapy.


Asunto(s)
Antineoplásicos Alquilantes/farmacología , Apoptosis/fisiología , Neoplasias de la Mama , Hipertermia Inducida , Hipoxia , Neovascularización Patológica , Animales , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/radioterapia , Moléculas de Adhesión Celular/metabolismo , Terapia Combinada , Citocinas/metabolismo , Factores de Crecimiento Endotelial/metabolismo , Endotelinas/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Factor VIII/metabolismo , Femenino , Ifosfamida/farmacología , Inmunohistoquímica , Linfocinas/metabolismo , Ratones , Ratones Desnudos , Factor de Crecimiento Nervioso/metabolismo , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular , Ensayos Antitumor por Modelo de Xenoinjerto
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