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1.
Ann Oncol ; 19(6): 1060-7, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18304965

RESUMEN

BACKGROUND: The antitumor activity of CS-1008, a humanized agonistic anti-human death receptor (DR) 5 antibody, was investigated in preclinical models. MATERIALS AND METHODS: Cytotoxicity of CS-1008 was evaluated in a several human tumor cell lines as well as primary human hepatocytes in vitro. To evaluate antitumor efficacy, athymic nude mice were inoculated with human colorectal tumor COLO 205, pancreatic tumor MIA PaCa-2 or non-small-cell lung carcinoma NCI-H2122 and CS-1008 was i.v. administered. The combination effects of CS-1008 with gemcitabine or docetaxel (Taxotere) against MIA PaCa-2 or NCI-H2122 were evaluated in vivo, respectively. RESULTS: CS-1008 inhibited the growth of tumor cell lines with DR5 expression, including COLO 205, NCI-H2122, MIA PaCa-2 and renal cell adenocarcinoma ACHN in vitro with antibody cross-linkage. Using COLO 205, apoptosis induction was confirmed by annexin V staining. Weekly administration of CS-1008 resulted in the inhibition of COLO 205 tumor growth as well as MIA PaCa-2 in vivo. CS-1008 in combination with gemcitabine or docetaxel demonstrated enhanced antitumor activity against MIA PaCa-2 or NCI-H2122 cells, respectively. Unlike tumor necrosis factor-related apoptosis-inducing ligand, CS-1008 did not induce cell death in human primary hepatocytes. CONCLUSION: CS-1008 has a selective toxicity toward tumor cells expressing DR5 and the potential for antitumor efficacy in human malignancies.


Asunto(s)
Anticuerpos/administración & dosificación , Antineoplásicos/administración & dosificación , Hepatocitos/efectos de los fármacos , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/inmunología , Animales , Anticuerpos Monoclonales/administración & dosificación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Docetaxel , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Taxoides/administración & dosificación , Gemcitabina
2.
Oncogene ; 25(16): 2304-17, 2006 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-16331265

RESUMEN

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists demonstrate antitumor activity likely through transactivating genes that regulate cell proliferation, apoptosis, and differentiation. The PAX8/PPARgamma fusion oncogene, which is common in human follicular thyroid carcinomas appears to act via dominant negative suppression of wild-type PPARgamma, suggesting that it may be a tumor suppressor gene in thyroid cells. We have identified a novel high-affinity PPARgamma agonist (RS5444) that is dependent upon PPARgamma for its biological activity. This is the first report of this molecule and its antitumor activity. In vitro, the IC50 for growth inhibition is approximately 0.8 nM while anaplastic thyroid carcinoma (ATC) tumor growth was inhibited three- to fourfold in nude mice. siRNA against PPARgamma and a pharmacological antagonist demonstrated that functional PPARgamma was required for growth inhibitory activity of RS5444. RS5444 upregulated the cell cycle kinase inhibitor, p21WAF1/CIP1. Silencing p21WAF1/CIP1 rendered cells insensitive to RS5444. RS5444 plus paclitaxel demonstrated additive antiproliferative activity in cell culture and minimal ATC tumor growth in vivo. RS5444 did not induce apoptosis but combined with paclitaxel, doubled the apoptotic index compared to that of paclitaxel. Our data indicate that functional PPARgamma is a molecular target for therapy in ATC. We demonstrated that RS5444, a thiazolidinedione (Tzd) derivative, alone or in combination with paclitaxel, may provide therapeutic benefit to patients diagnosed with ATC.


Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/fisiología , PPAR gamma/agonistas , Paclitaxel/administración & dosificación , Tiazolidinedionas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromanos/farmacología , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/biosíntesis , Femenino , Humanos , Ratones , PPAR gamma/fisiología , Tiazolidinedionas/administración & dosificación , Tiazolidinedionas/farmacología , Neoplasias de la Tiroides/patología , Troglitazona
5.
Carbohydr Res ; 324(4): 225-30, 2000 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-10744331

RESUMEN

The synthesis of lipid A-type pyrancarboxylic acid derivatives, which have a carboxylic acid group in the anomeric position of the reducing part of the disaccharide instead of the phosphate group in lipid A, is described. One of the compounds thus synthesized, which has an acyl substitution pattern similar to that of Escherichia coli lipid A, showed lipopolysaccharide (LPS)-agonistic activity. The other, which contains four lipid chains in the molecule, exhibited strong LPS-antagonistic activity toward human monoblastic U937 cells.


Asunto(s)
Lípido A/análogos & derivados , Conformación de Carbohidratos , Ácidos Carboxílicos/síntesis química , Disacáridos/síntesis química , Escherichia coli , Humanos , Lípido A/farmacología , Lipopolisacáridos/química , Espectroscopía de Resonancia Magnética , Piranos/síntesis química , Factor de Necrosis Tumoral alfa/metabolismo , Células U937
7.
Cancer Res ; 59(22): 5695-703, 1999 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-10582687

RESUMEN

Base-unpairing regions (BURs) contain a specialized DNA context with an exceptionally high unwinding propensity, and are typically identified within various matrix attachment regions. A BUR affinity column was used to purify a doublet of Mr 20,000 proteins from human breast carcinoma cells. These proteins were identified as the high-mobility group (HMG) protein, HMG-I, and its splicing variant, HMG-Y. We show that HMG-I(Y) specifically binds BURs. Mutating BURs so as to abrogate their unwinding property greatly reduced their binding affinity to HMG-I(Y). Numerous studies have indicated that elevated HMG-I(Y) expression is correlated with more advanced cancers and with increased metastatic potential. We studied whether the expression of HMG-I(Y) responds to signaling through the heregulin (HRG)-erbB pathway and the extracellular matrix. HMG-I(Y) expression was increased in MCF-7 cells after stable transfection with an HRG expression construct that led cells to acquire estrogen independence and metastasizing ability. A high level of HMG-I(Y) expression was detected in metastatic MDA-MB-231 cells, but the expression was virtually diminished, and the metastasizing ability was lost after cells were stably transfected with an antisense HRG cDNA construct. HMG-I(Y) was also decreased in MDA-MB-231 cells when treated with a chemical inhibitor for matrix metalloproteinase-9 that led to a reduction of invasive capability in vitro. The level of HMG-I(Y) expression, therefore, is dynamically regulated in human breast cancer cells in response to varying types of signaling that affect metastatic ability, including the HRG-erbB pathway and those from the extracellular matrix.


Asunto(s)
Neoplasias de la Mama/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas del Grupo de Alta Movilidad/metabolismo , Proteínas de Neoplasias/metabolismo , Neurregulina-1/metabolismo , Ribonucleoproteínas/metabolismo , Factores de Transcripción/metabolismo , Elementos sin Sentido (Genética)/administración & dosificación , Elementos sin Sentido (Genética)/genética , Southern Blotting , Western Blotting , Neoplasias de la Mama/química , Neoplasias de la Mama/patología , Proteínas de Unión al ADN/genética , Estrógenos/farmacología , Femenino , Proteína HMGA1a , Ribonucleoproteínas Nucleares Heterogéneas , Proteínas del Grupo de Alta Movilidad/genética , Proteínas del Grupo de Alta Movilidad/aislamiento & purificación , Humanos , Inhibidores de la Metaloproteinasa de la Matriz , Peso Molecular , Metástasis de la Neoplasia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/aislamiento & purificación , Neurregulina-1/genética , Fenotipo , Ribonucleoproteínas/genética , Factores de Transcripción/genética , Factores de Transcripción/aislamiento & purificación , Transfección , Células Tumorales Cultivadas/efectos de los fármacos
8.
Life Sci ; 65(12): 1287-96, 1999.
Artículo en Inglés | MEDLINE | ID: mdl-10503944

RESUMEN

Recent investigations suggest that cytotoxic cytokines such as tumor necrosis factor (TNF)alpha and interleukin (IL)-1beta or free radicals play an essential role in destruction of pancreatic beta cells in Type 1 diabetes and that, therefore, anti-oxidant or anti-TNF alpha and IL-1beta therapy could prevent the development of Type I diabetes. Troglitazone belongs to a novel class of antidiabetic agent possessing the ability to enhance insulin action provably through activating PPAR gamma and to scavenge free radicals. In the present study, we examined whether troglitazone can prevent the development of Type 1 diabetes in multiple, low-dose streptozotocin (MLDSTZ)-injected mice. In addition, effects of troglitazone on cytokine-induced pancreatic beta cell damage were examined in vitro. Type 1 diabetes was induced by MLDSTZ injection to DBA/2 mice (40 mg/kg/day for 5 days). Troglitazone was administered as a 0.2% food admixture (240 mg/kg/day) for 4 weeks from the start of or immediately after STZ injection. MLDSTZ injection elevated plasma glucose to 615 +/- 8 mg/dl 4 weeks after final STZ injection and was accompanied by infiltration of leukocytes to pancreatic islets (insulitis). Troglitazone treatment with MLDSTZ injection prevented hyperglycemia (230 +/- 30 mg/dl) and, suppressed insulitis and TNF alpha production from intraperitoneal exudate cells. TNF alpha (10 pg/ml) and IL-1beta (1 pg/ml) addition to hamster insulinoma cell line HIT-T15 for 7 days in vitro decreased insulin secretion and cell viability. Simultaneous troglitazone addition (0.03 to approximately 3 microM) significantly improved cytokine-induced decrease in insulin secretion and in cell viability. These findings suggest that troglitazone prevents the development of Type 1 diabetes in the MLDSTZ model by suppressing insulitis associated with decreasing TNF alpha production from intraperitoneal exudate cells and the subsequent TNF alpha and IL-1beta-induced beta cell damage.


Asunto(s)
Cromanos/uso terapéutico , Diabetes Mellitus Experimental/prevención & control , Diabetes Mellitus Tipo 1/prevención & control , Depuradores de Radicales Libres/uso terapéutico , Hipoglucemiantes/uso terapéutico , Tiazoles/uso terapéutico , Tiazolidinedionas , Animales , Glucemia/análisis , Cricetinae , Insulina/sangre , Islotes Pancreáticos/patología , Ratones , Ratones Endogámicos DBA , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II , Estreptozocina , Troglitazona , Factor de Necrosis Tumoral alfa/biosíntesis
9.
Int J Cancer ; 82(2): 226-36, 1999 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-10389757

RESUMEN

We have studied the antitumor activity and the novel DNA-self-strand-breaking mechanism of CNDAC (1-(2-Ccyano-2-deoxy-beta-D-arabino-pentofuranosyl)cytosine) and its N4-palmitoyl derivative (CS-682). In vitro, CS-682 showed strong cytotoxicity against human tumor cells comparable with that of CNDAC; both compounds displayed a similar broad spectrum. In vivo, however, orally administered CS-682 showed a more potent activity against human tumor xenografts than CNDAC, 5'-deoxy-5-fluorouridine, 5-fluorouracil and 2',2'-difluorodeoxycytidine. Moreover, CS-682 was effective against various human organ tumor xenografts at a wide dose range and with low toxicity, and was effective against P388 leukemic cells resistant to mitomycin-C, vincristine, 5-fluorouracil or cisplatin in syngeneic mice. CNDAC, an active metabolite of CS-682, had a prolonged plasma half-life after repeated oral administrations of CS-682 but not after oral administrations of CNDAC itself. This difference may partially explain the higher antitumor activity of CS-682 relative to CNDAC. In both CNDAC- and CS-682-treated carcinoma cells, CNDAC 5'-triphosphate (CNDACTP) was generated and incorporated into a DNA strand. High performance liquid chromatography (HPLC) and mass spectrometric analysis of the nucleosides prepared by digestion of the DNA from the CNDAC-treated cells detected ddCNC (2'-Ccyano-2',3 '-didehydro-2',3 '-dideoxycytidine), which was shown to be generated only when the self-strand-breakage of CNDACTP-incorporated DNA occurred. The cytotoxicity of CNDAC was completely abrogated by the addition of 2'-deoxycytidine and was low against cells with decreased deoxycytidine kinase. Our results suggest that CNDAC is converted to CNDACMP by deoxycytidine kinase and that the resulting CNDACTP incorporated into a DNA strand as CNDACMP may induce DNA-self-strand-breakage. This novel DNA-self-strand-breaking mechanism may contribute to the potent antitumor activity of CS-682.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Arabinonucleósidos/farmacología , Citarabina/análogos & derivados , Citosina/análogos & derivados , Daño del ADN , ADN de Neoplasias/efectos de los fármacos , Neoplasias Experimentales/tratamiento farmacológico , Administración Oral , Animales , Antimetabolitos Antineoplásicos/uso terapéutico , Arabinonucleósidos/uso terapéutico , Biotransformación , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Cisplatino/farmacología , Citarabina/farmacología , Citarabina/uso terapéutico , Citosina/farmacología , Citosina/uso terapéutico , Desoxicitidina/farmacología , Desoxicitidina Quinasa/metabolismo , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Fluorouracilo/uso terapéutico , Humanos , Células KB/efectos de los fármacos , Leucemia P388/tratamiento farmacológico , Leucemia P388/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Ratones Desnudos , Mitomicina/farmacología , Estructura Molecular , Proteínas de Neoplasias/metabolismo , Trasplante de Neoplasias , Ratas , Ratas Desnudas , Organismos Libres de Patógenos Específicos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Células Tumorales Cultivadas/efectos de los fármacos , Vincristina/farmacología
10.
Kidney Int Suppl ; 71: S97-100, 1999 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10412748

RESUMEN

BACKGROUND: The mevalonate pathway is important for the biosynthesis of isoprenoids such as geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) as well as cholesterol. It has been reported that treatment with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor ameliorates glomerular injury in several experimental models of progressive glomerular disease. The present investigation was performed to elucidate the role of mevalonate metabolites in mesangial cell proliferation and extracellular matrix accumulation. METHOD: Cycling or quiescent human mesangial cells were incubated in RPMI1640 containing 10% heat-inactivated fetal calf serum (FCS) in the absence or presence of pravastatin, an inhibitor of HMG-CoA reductase, and mevalonate metabolites. Type IV collagen secretion and mRNA expression, [3H]-thymidine incorporation was measured. Cell cycle phases were monitored by flow cytometry. RESULTS: Pravastatin inhibited FCS-stimulated type IV collagen secretion (IC50 = 210 microM) and mRNA expression. Pravastatin also inhibited FCS-stimulated [3H]-thymidine incorporation (IC50 = 430 microM). Analysis with flow cytometry revealed that pravastatin inhibited G1 to S phase transition of FCS-stimulated mesangial cells. Mevalonate reversed these inhibitory effects of pravastatin completely. Among two major metabolities of mevalonate, GGPP and FPP, only GGPP reversed pravastatin-induced inhibition of type IV collagen secretion, DNA synthesis and G1 to S phase progression. CONCLUSION: The present results suggest that GGPP plays a critical role in the type IV collagen secretion and G1 to S phase transition in FCS-stimulated human mesangial cells.


Asunto(s)
Colágeno/efectos de los fármacos , Mesangio Glomerular/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Pravastatina/farmacología , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Células Cultivadas , Colágeno/genética , Colágeno/metabolismo , ADN/biosíntesis , ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Expresión Génica/efectos de los fármacos , Mesangio Glomerular/citología , Mesangio Glomerular/metabolismo , Humanos , Ácido Mevalónico/metabolismo , Ácido Mevalónico/farmacología , Fosfatos de Poliisoprenilo/farmacología , ARN Mensajero/genética , Sesquiterpenos
11.
Kidney Int ; 55(2): 520-8, 1999 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-9987076

RESUMEN

BACKGROUND: The mevalonate pathway is important for the biosynthesis of isoprenoids such as geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate, as well as cholesterol. It has been reported that treatment with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor ameliorates glomerular injury in several experimental models of progressive glomerular disease. However, the effect of HMG-CoA reductase inhibitor on mesangial cell function has not been fully understood. This investigation was performed to elucidate the role of a mevalonate metabolite(s) in mesangial cell proliferation and extracellular matrix accumulation. METHODS: Cycling or quiescent human mesangial cells were incubated in RPMI 1640 containing 10% heat-inactivated fetal calf serum (FCS) in the absence or presence of pravastatin, an inhibitor of HMG-CoA reductase, and mevalonate metabolites. Type IV collagen secretion, mRNA expression, and [3H]thymidine incorporation were measured. Cell cycle phases were monitored by flow cytometry. RESULTS: Pravastatin inhibited FCS-stimulated type IV collagen secretion (IC50 = 210 microM) and mRNA expression. Pravastatin also inhibited FCS-stimulated [3H]thymidine incorporation (IC50 = 430 microM). Analysis with flow cytometry revealed that pravastatin inhibited the G1 to S phase transition of FCS-stimulated mesangial cells. Mevalonate reversed these inhibitory effects of pravastatin completely. Among two major metabolites of mevalonate, GGPP and farnesylpyrophosphate, only GGPP reversed pravastatin-induced inhibition of type IV collagen secretion, DNA synthesis, and the G1 to S phase progression. CONCLUSIONS: These results suggest that GGPP plays critical roles for the type IV collagen secretion and G1 to S phase transition in FCS-stimulated human mesangial cells.


Asunto(s)
Colágeno/metabolismo , Mesangio Glomerular/citología , Mesangio Glomerular/metabolismo , Fosfatos de Poliisoprenilo/metabolismo , Animales , Bovinos/sangre , Bovinos/embriología , Ciclo Celular/efectos de los fármacos , División Celular/fisiología , Células Cultivadas , Colágeno/genética , ADN/biosíntesis , Sangre Fetal/fisiología , Expresión Génica/efectos de los fármacos , Mesangio Glomerular/efectos de los fármacos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Ácido Mevalónico/metabolismo , Pravastatina/farmacología
12.
Immunopharmacology ; 34(1): 51-61, 1996 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-8880225

RESUMEN

It has been shown previously that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA RIs) such as compactin and lovastatin suppress human lymphocyte functions in vitro (Cuthbert and Lipsky, 1981; Cutts and Bankhurst, 1989). Although it is not fully understood what inhibitory role the HMG-CoA RIs perform in causing this suppression, we show in this study that a certain inhibition threshold (inhibition level > 90%) of lymphocytic HMG-CoA reductase is required for the HMG-CoA RIs to attain effective inhibitory action in human lymphocyte lymphocyte functions in vitro. Thus the inhibitory activity of simvastatin, a lipophilic inhibitor, on sterol synthesis (HMG-CoA reductase activity) in lymphocytes was as much as 430 times more potent than that of pravastatin sodium, a hydrophilic inhibitor (IC50; 0.013 microM and 5.6 microM, respectively), and although pravastatin sodium and simvastatin at concentration levels of 10 and 0.016 microM respectively, inhibited the sterol synthesis in just over 50%, they failed to inhibit the lymphocyte functions. Significant inhibition (P < 0.01) of lymphocyte functions, including lymphocyte proliferative response to a variety of stimuli and activated natural killer-cell cytotoxicity, was demonstrated only when greater than 90% of the sterol synthesis in lymphocytes was inhibited by either simvastatin or simvastatin sodium salt at concentrations above 2 microM. This simvastatin-induced inhibition of lymphocyte functions was almost completely reversed by the addition of a 1 mM solution of mevalonate. Although simvastatin at a lower clinical blood concentration of 0.016 microM failed to inhibit either lymphocyte functions or HMG-CoA reductase activity sufficiently, at this level it caused a significant increase in cyclosporin A-induced suppression of T-cell response. These results infer that insufficient inhibition (in the 50% region) of HMG-CoA reductase activity by a low clinical blood concentration of HMG-CoA RIs, could still render the lymphocytes susceptible to immunosuppressive treatments. Pravastatin sodium on the other hand, is inactive in inhibiting lymphocyte functions in vitro, and such inactivity can be explained solely of the basis of its failure to inhibit HMG-CoA reductase activity in lymphocytes sufficiently.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Lovastatina/análogos & derivados , Linfocitos/efectos de los fármacos , Linfocitos/fisiología , Pravastatina/farmacología , Esteroles/biosíntesis , Ciclosporina/farmacología , Humanos , Inmunosupresores/farmacología , Interleucina-2/farmacología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Lovastatina/farmacología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Prueba de Cultivo Mixto de Linfocitos , Linfocitos/inmunología , Ácido Mevalónico/farmacología , Fitohemaglutininas/farmacología , Simvastatina
13.
Carbohydr Res ; 283: 27-51, 1996 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-8901261

RESUMEN

As part of our ongoing study to survey potent LPS antagonists, the following six compounds were synthesized in an efficient manner: 3-carboxypropyl and carboxymethyl 2-deoxy-2-(2,2-difluorotetradecanamido)-4-O-phosphono-3-O-[(R)-3- (tetradecanoyloxy)tetradecanoyl]-alpha- and beta-D-glucopyranosides (11 and 23; 32 and 36), as well as the non-fluorinated equivalents, carboxymethyl 2-deoxy-4-O-phosphono-2-tetradecanamido-3-O-[(R)-3-(tetradecano yloxy)- tetradecanoyl]-alpha-D-glucopyranoside (44) and carboxymethyl 2-deoxy-2-[(R)-3-(hydroxy)tetradecanamido]-4-O-phosphono-3-O-[(R)- 3- (tetradecanoyloxy)tetradecanoyl]-alpha-D-glucopyranoside (48). Of these compounds, 32 was most pronounced in terms of LPS-antagonistic activity.


Asunto(s)
Glucósidos/síntesis química , Conformación de Carbohidratos , Secuencia de Carbohidratos , Células Cultivadas , Escherichia coli/química , Glucósidos/farmacología , Glucolípidos/farmacología , Lípido A/análogos & derivados , Lípido A/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Estructura Molecular , Prednisolona/farmacología , Salmonella/química , Factor de Necrosis Tumoral alfa/metabolismo
14.
J Immunol ; 155(10): 4926-32, 1995 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-7594497

RESUMEN

In the present study, we demonstrate that TGF-beta is capable of enhancing macrophage ability to produce IL-10 in normal and EL4 tumor-bearing mice. We found the increase in IL-10 in ascitic fluid and IL-10 mRNA expression in macrophages in parallel with the TGF-beta level and tumor progression. The macrophage production of IL-10 in the tumor-bearing mice was significantly enhanced without LPS stimulation in vitro, compared with normal controls. To clarify the mechanism wherein increased IL-10 production was induced, anti-TGF-beta or anti-IL-10 Abs were administered to EL4-bearing mice. Administration of anti-TGF-beta Ab led to a reduction in the IL-10 contents in ascitic fluid of tumor-bearing mice; however, anti-IL-10 Ab administration did not prevent the increase in TGF-beta contents. Enhanced IL-10 production and mRNA expression of macrophages from the tumor-bearing mice were also reduced by anti-TGF-beta Ab administration. Both anti-TGF-beta and anti-IL-10 Ab administration restored the TNF-alpha production by macrophages in EL4-bearing mice. In normal macrophages, in vitro pretreatment with TGF-beta 1 potentiated IL-10 production, and when natural TGF-beta 1 was administered to normal mice, the recovered peritoneal macrophages showed enhanced IL-10 production. Based on the above findings it can be concluded that TGF-beta enhances macrophage ability to produce IL-10, which sheds a new light on the role of TGF-beta in the immune system.


Asunto(s)
Interleucina-10/biosíntesis , Macrófagos Peritoneales/inmunología , Timoma/inmunología , Factor de Crecimiento Transformador beta/biosíntesis , Animales , Secuencia de Bases , Células Cultivadas , Femenino , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , ARN Mensajero/biosíntesis , Timoma/patología , Factor de Crecimiento Transformador beta/farmacología
16.
Cancer Immunol Immunother ; 33(2): 71-9, 1991.
Artículo en Inglés | MEDLINE | ID: mdl-1828007

RESUMEN

RS-0481, (4R)-3-benzoyl-N-[(1R)-phenylethyl]-4-thiazolidinecarboxamide, is a compound that can re-establish the function of certain lymphoid cell populations impaired by the presence of a growing tumor in an animal. The compound markedly augmented the tumor-specific cytotoxic T lymphocytes, TDTH (delayed-type hypersensitivity T cells), and the nonspecific lymphokine-activated-killer-cell-like cell responses. It also enhanced the tumor-inhibitory effect of macrophages in tumor-bearing mice, but not in normal mice, indicating that it enhances the antitumor immune responses. Lymphocytes from RS-0481-treated tumor-bearing mice released significantly higher amounts of macrophage-activating factor(s) (MAF) and interleukin-2(IL-2)-like factors in culture compared with lymphocytes from untreated animals. Also, sera from treated tumor bearers showed elevated colony-stimulating factor (CSF) activity. Although the compound did not influence the factor-producing activity in mice without tumor, it enhanced the responsiveness of their bone marrow cells, T cells, and macrophages to CSF, IL-2, and MAF. It seems therefore possible that the compound enhances the responsiveness of immunocompetent cells to cytokines, resulting in a marked augmentation of antitumor T cell responses in tumor-bearing mice. Consistently it inhibited the development of lymph node metastasis of transplanted X5563 plasmacytoma, and we showed that T cells play a decisive role in this inhibition. The compound also counteracted the development of suppressor T cell activity in the spleen of tumor-bearing mice.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Neoplasias Experimentales/inmunología , Tiazoles/farmacología , Animales , Médula Ósea/efectos de los fármacos , Factores Estimulantes de Colonias/biosíntesis , Factores Estimulantes de Colonias/farmacología , Femenino , Hipersensibilidad Tardía , Interleucina-2/biosíntesis , Interleucina-2/farmacología , Células Asesinas Naturales/efectos de los fármacos , Activación de Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos C3H , Metástasis de la Neoplasia , Linfocitos T/efectos de los fármacos , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Tiazolidinas
17.
Cell Immunol ; 123(1): 134-47, 1989 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-2550147

RESUMEN

The P3HR-1 Burkitt lymphoma line carries the Epstein-Barr virus (EBV) genome and a small proportion of the cells (1-3%) enter the lytic cycle spontaneously. Treatment with TPA and n-butyrate elevates considerably the number of virus-producing cells (25-35%). Cells which enter the lytic cycle express the EBV early antigen EA, the viral capsid antigen VCA, and the membrane antigen MA. Antibodies against these antigens are present in EBV-immune human sera. The expression of virus envelope protein on the plasma membrane renders the cells sensitive to immune effector mechanisms. These were shown to be initiated by the alternative complement pathway (ACP)-activating capacity of the cells and by their reactivity with antibodies directed to the MA. When incubated with EBV-immune or nonimmune human serum, the induced (P3HR-1-V) cells activated C3 through ACP and fixed the generated C3 fragments. The efficiency of opsonization was higher in immune serum. By varying the experimental conditions we showed the damage of the induced cells by the complement system and by blood lymphocytes, and analysed the involvement of antibodies and the activated C3 fragments in the lymphocyte-mediated lysis. P3HR-1-V cells were lysed by immune serum and also by nonimmune serum though with lower efficiency. The induced cells had elevated sensitivity to the NK effect which was potentiated if the conditions allowed their opsonization. In the presence of antibodies the lymphocyte-mediated lysis was considerably higher and the ADCC mechanism was also potentiated by opsonization. These experiments suggest that B cells which enter the virus-producing cycle may be eliminated in EBV nonimmune host by NK cells. After the antibody response against the virus develops, the attack on these cells is more efficient through complement and lymphocyte-mediated antibody-dependent mechanisms. These effector mechanisms are enhanced by opsonization which is the consequence of the C3-activating capacity of the cells. The multiple ways of the immune attack on the B cells prepared to produce EBV may explain the absence of EA and VCA positive B cells in tumor cell populations and during the acute phase of infectious mononucleosis.


Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos , Linfocitos B/inmunología , Linfoma de Burkitt/inmunología , Herpesvirus Humano 4/inmunología , Activación de Linfocitos , Anticuerpos Monoclonales , Línea Celular , Complemento C3/metabolismo , Vía Alternativa del Complemento , Citotoxicidad Inmunológica , Técnica del Anticuerpo Fluorescente , Herpesvirus Humano 4/crecimiento & desarrollo , Humanos , Inmunidad Celular , Células Tumorales Cultivadas
18.
Jpn J Pharmacol ; 46(1): 86-9, 1988 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-3285064

RESUMEN

Oral treatment of female NZB/NZW F1 hybrid mice with captopril prevented the development of proteinuria and prolonged survival in mice demonstrating slight (trace to 1+) proteinuria. Captopril treatment also markedly reduced the incidence and magnitude of proteinuria and prevented death in mice showing significant (3+ or greater) proteinuria. Histopathological studies of the kidneys of treated mice further demonstrated improvements in the renal lesions of autoimmune mice. The mechanisms whereby captopril treatment influences the course of disease in NZB/NZW mice are not known.


Asunto(s)
Captopril/farmacología , Proteinuria/tratamiento farmacológico , Animales , Femenino , Riñón/patología , Ratones , Ratones Endogámicos NZB , Proteinuria/mortalidad
19.
Cell Immunol ; 105(2): 340-54, 1987 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-2436809

RESUMEN

The specificities of cytotoxic T lymphocytes (CTL) were studied for the analysis of CTL against tumor-specific cell surface antigen(s) (TSSA) of non-virus-producing tumor cells induced by the Schmidt-Ruppin strain of Rous sarcoma virus (SR-RSV) in B10 congenic and recombinant mice. Eight CTL clones were established from immune spleen cells of B10.A(5R) mice. These clones demonstrated six patterns of cytotoxic reactivity in vitro: Two clones showed H-2 restriction in tumor cell lysis. Two other clones had the capacity to lyse syngeneic, H-2K-compatible B10 and H-2-incompatible B10.A(4R) tumor cells, but not YAC-1 cells. One clone had cytotoxic activity against syngeneic, H-2D-compatible B10.D2 tumor cells and YAC-1 cells, but not against H-2-incompatible tumor cells. One clone had cytotoxic activity against syngeneic and YAC-1 tumor cells, but not against either H-2-compatible or H-2-incompatible tumor cells. One clone had lytic activity to syngeneic, H-2-compatible, H-2-incompatible, and YAC-1 tumor cells. Another clone killed H-2-incompatible B10.A(4R) tumor and YAC-1 cells, but not syngeneic or H-2-compatible tumor cells. All these clones strongly expressed surface Thy-1.2 antigens, whereas the expression of Lyt-1.2 and Lyt-2.2 antigens was different from clone to clone. These results demonstrate heterogeneity of both lytic specificity and phenotype of CTL against RSV-induced mouse tumor cells, suggesting the existence of multiple antigenic sites on the RSV TSSA recognized by CTL populations.


Asunto(s)
Antígenos de Neoplasias/inmunología , Antígenos Virales/administración & dosificación , Virus del Sarcoma Aviar/inmunología , Citotoxicidad Inmunológica , Antígenos H-2/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Antígenos de Diferenciación de Linfocitos T , Antígenos Heterófilos/inmunología , Antígenos de Superficie/inmunología , Antígenos Virales/inmunología , Línea Celular , Células Clonales , Proteínas del Sistema Complemento/fisiología , Epítopos/inmunología , Femenino , Interleucina-2/inmunología , Isoanticuerpos/administración & dosificación , Isoanticuerpos/inmunología , Ratones , Ratones Endogámicos , Fenotipo , Factores de Tiempo
20.
Jpn J Cancer Res ; 76(5): 400-13, 1985 May.
Artículo en Inglés | MEDLINE | ID: mdl-2989065

RESUMEN

An immunogenetic evaluation of the antitumor activity of the immunopotentiator Nocardia rubra cell-wall skeleton (N. rubra-CWS) has been performed using non-virus-producing tumors induced by the Schmidt-Ruppin strain of Rous sarcoma virus (RSV) in B10 congenic and recombinant mice. Live tumor cells mixed with either N. rubra-CWS or a placebo control were inoculated intradermally into the right flank of syngeneic mice. With N. rubra-CWS, the development and growth of B10 mouse tumors, S1018(B10) and B10SA2F, in B10(H-2b) mice were completely inhibited in all test mice. B10.A(5R) mouse tumor, S322(5R), was completely suppressed in 23 of 25 B10.A(5R)(H-2i5) mice, and B10.BR mouse tumor, S623(BR), was completely suppressed in 7 of 14 B10.BR(H-2k) mice. However, B10.D2 mouse tumor, S908(D2), in B10.D2(H-2d) mice and B10.A mouse tumors, S826(BA) and B10ABr1F, in B10.A(H-2a) mice were not suppressed at all by N. rubra-CWS. N. rubra-CWS showed a remarkable antitumor effect in B10 mice, not only in mixed inoculation with the tumor cells but also with intratumoral administration. These effects were not seen in B10.A mice. Peritoneal exudate cells (PEC) from B10 and B10.A strains previously treated intraperitoneally with N. rubra-CWS and/or MMC-treated tumor cells showed cytolytic and cytostatic activities on tumor cells derived from both strains. These results did not reflect the strain difference seen in the in vivo studies. Mitogenic activity of N. rubra-CWS on spleen cells, however, was significantly different among B10 congenic mice; N. rubra-CWS induced greater blastogenesis of spleen cells from B10 mice than of those from B10.A mice, corresponding to the in vivo results showing strain difference. These results suggest that the host's immunogenetic background may play an important role in cancer therapy with immunopotentiators.


Asunto(s)
Adyuvantes Inmunológicos , Pared Celular/inmunología , Nocardia/inmunología , Sarcoma Experimental/terapia , Animales , Ascitis/inmunología , Ascitis/patología , Virus del Sarcoma Aviar , Células Cultivadas , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C/genética , Ratones Endogámicos C57BL , Mitógenos , Sarcoma Experimental/inmunología , Especificidad de la Especie
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