RESUMEN
Serious infectious diseases, accompanied by macrophage-dominated chronic inflammation, are common in farmed Atlantic cod. To increase knowledge relating to morphological aspects of such inflammatory responses, cod were challenged with Francisella noatunensis, an important bacterial pathogen of this fish species. Tissue and cell dynamics in the spleen were examined sequentially over 60 days. Small clusters of mainly macrophage-like cells (MLCs) staining for non-specific esterase and acid phosphatase developed with time. These foci were transiently infiltrated by pleomorphic proliferating cells of unknown nature and by granulocyte-like cells (GCLCs) staining for peroxidase and lysozyme. The latter cell type, which appeared to be resident in the red pulp of control fish, migrated into the inflammatory foci of infected fish. Cells expressing genes encoding IFN-γ and IL-8 increased in number during the study period. Bacteria were detected only in the MLCs and their number increased despite the extensive inflammation. Our results demonstrate an intimate spatial relationship in inflammatory foci between at least three cell types. The presence of GCLCs, together with MLCs, suggests pyogranulomatous inflammation as a more appropriate descriptive term than granulomatous inflammation.
Asunto(s)
Enfermedades de los Peces/microbiología , Enfermedades de los Peces/patología , Francisella , Gadus morhua , Infecciones por Bacterias Gramnegativas/veterinaria , Inflamación/veterinaria , Bazo/citología , Animales , Técnica del Anticuerpo Fluorescente/veterinaria , Infecciones por Bacterias Gramnegativas/patología , Granulocitos/citología , Granulocitos/metabolismo , Técnicas Histológicas/veterinaria , Inmunohistoquímica/veterinaria , Hibridación in Situ/veterinaria , Inflamación/patología , Interferón gamma/metabolismo , Interleucina-8/metabolismo , Macrófagos/citología , Macrófagos/metabolismoAsunto(s)
Antineoplásicos/uso terapéutico , Janus Quinasa 2/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Mutación , Piperazinas/uso terapéutico , Policitemia/etiología , Pirimidinas/uso terapéutico , Adulto , Benzamidas , Humanos , Mesilato de Imatinib , MasculinoRESUMEN
Several lines of evidence have postulated that reduction in the activity of lipoprotein lipase (LPL) is involved in cachexia induction in cancer patients. Recently we have demonstrated that murine melanoma B16 has the ability to reduce the LPL activity and thereby induce cachexia symptoms in mice following intraperitoneal inoculation. In order to further investigate the relationship between LPL activity and cachectic syndrome, cachexia models other than melanoma B16 are required. However, there are few animal cachexia models in which LPL activity is involved in the induction of cachectic symptoms. In this study, cachectic symptoms and plasma LPL activity were investigated in mice bearing EL-4 mouse lymphoma. In EL-4 bearing mice the body weight including tumor weight in the abdominal cavity was rather higher than that of normal mice without tumor, whereas weights of carcass wet and gastrocnemius muscle were significantly decreased in EL-4 bearing mice. Elevated blood levels of triglyceride and non-esterified fatty acid were observed in mice bearing EL-4, associated with the impaired plasma LPL activity. Overall, this study indicated that EL-4 lymphoma in mice results in a severe cachexia which is possibly related to impaired LPL activity and also provided a useful cachexia model for understanding the role of LPL in the development of cancer cachexia.
Asunto(s)
Caquexia/enzimología , Lipoproteína Lipasa/metabolismo , Linfoma/enzimología , Animales , Caquexia/complicaciones , Caquexia/fisiopatología , Linfoma/complicaciones , Linfoma/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Células Tumorales CultivadasRESUMEN
Dapsone (4,4'-diaminodiphenyl sulphone), an antileprotic and antimalarial drug, has been reported to be of therapeutic benefit in idiopathic thrombocytopenic purpura in the clinic. However, adverse reactions such as haemolytic anaemia have often been observed. In this study, we found that dapsone increased the number of platelets and decreased the number of red blood cells in male (NZWxBXSB)F1 (W/BF1) mice, an animal model of idiopathic thrombocytopenic purpura. In studies to prepare derivatives of dapsone with weaker side effects than the parent compound, FR115092 (2-[5-(2-pyridylsulphonyl)thiazolyl]amine) was discovered. The effect of FR115092 on the number of blood cells was studied and compared with dapsone in mice. FR 115092 increased the number of platelets without reducing the number of red blood cells in W/BF1 mice. This drug significantly suppressed the increase in circulating autoantibodies against platelets and increased the number of megakaryocytes. Furthermore, FR115092 inhibited the reduction of the number of platelets in mitomycin C-induced thrombocytopenic mice, as a consequence of its enhancement of growth and maturation of megakaryocytes. These findings suggest that FR115092 may be effective against various thrombocytopenias, without inducing haemolytic anaemia.
Asunto(s)
Autoinmunidad/efectos de los fármacos , Mitomicina/efectos adversos , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Piridinas/farmacología , Tiazoles/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Autoanticuerpos/sangre , Autoanticuerpos/efectos de los fármacos , Plaquetas/inmunología , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de los fármacos , Dapsona/farmacología , Recuento de Eritrocitos/efectos de los fármacos , Femenino , Masculino , Megacariocitos/citología , Megacariocitos/efectos de los fármacos , Ratones , Ratones Endogámicos , Recuento de Plaquetas/efectos de los fármacos , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/inducido químicamente , Trombopoyetina/farmacología , Factores de TiempoRESUMEN
Lipoprotein lipase (LPL) is a key regulatory enzyme responsible for the hydrolysis of triglyceride (TG)-rich lipoproteins. The reduction in LPL activity is observed in tumor bearing animals and cancer patients with cachectic symptoms, suggesting an involvement of LPL in inducing cancer cachexia. During a screening program for anti-cachectic agents we found that ponalrestat, an aldose reductase inhibitor, activates LPL activity. Ponalrestat increased the activity of LPL in adipose tissue in mice. The effect of ponalrestat on B16 melanoma-induced cachectic symptoms was next investigated in mice. The decrease in the weight of epididymal fat, carcass and whole body lipid was observed in mice following intraperitoneal inoculation of B16, compared to mice without the tumor inoculation. Treatment with ponalrestat resulted in the attenuation of the decrease in the tissue weight. The increase in the levels of TG and non-esterified fatty acid, and a decrease in the level of glucose in the blood, which was induced by the presence of tumor, were also restored to those of normal mice following ponalrestat treatment. The reduction in locomotor activity in tumor bearing mice was partially restored by the treatment with ponalrestat. Overall, this study demonstrated that ponalrestat, an aldose reductase inhibitor, possesses potent LPL activating activity and that the cachexia induced by B16 melanoma was alleviated by treatment with 'ponalrestat, suggesting that ponalrestat, a LPL activating agent, has a therapeutic potential for the treatment of cancer cachexia.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Caquexia/prevención & control , Inhibidores Enzimáticos/farmacología , Lipoproteína Lipasa/metabolismo , Melanoma Experimental/complicaciones , Ftalazinas/farmacología , Células 3T3 , Animales , Activación Enzimática/efectos de los fármacos , Femenino , Lípidos/análisis , Masculino , Melanoma Experimental/metabolismo , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , ConejosRESUMEN
Our recent study has demonstrated that ponalrestat, an aldose reductase inhibitor, activates lipoprotein lipase (LPL) activity in the adipose tissue and alleviates the cachectic symptoms induced by B16 melanoma in mice. In this study, the effect of ponalrestat on cachexia symptoms in nude mice bearing human melanomas G361 and SEKI was investigated because it has been suggested that the suppression of LPL has an important role in cachexia induction by these two melanomas in nude mice. Mice bearing G361 subcutaneously did not gain weight and became cachectic, associated with the tumor growth. Tumor growth was not affected by ponalrestat, nevertheless treatment with ponalrestat resulted in an amelioration of the reduction in the weight of body mass, epididymal fat, gastrocnemius muscle, carcass and whole body lipid induced by the presence of G361. A severe weight loss observed in nude mice bearing SEKI was also partially attenuated by ponalrestat treatment. Overall, this study showed that ponalrestat is effective in the attenuation of the cachectic symptoms induced by human melanomas G361 and SEKI in nude mice, suggesting that ponalrestat has a potential usefulness for the treatment of cancer cachexia.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Caquexia/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Interleucina-6 , Melanoma/complicaciones , Ftalazinas/farmacología , Animales , Peso Corporal/efectos de los fármacos , Caquexia/enzimología , Caquexia/etiología , Ingestión de Alimentos/efectos de los fármacos , Inhibidores Enzimáticos/química , Epidídimo/efectos de los fármacos , Inhibidores de Crecimiento/biosíntesis , Humanos , Factor Inhibidor de Leucemia , Linfocinas/biosíntesis , Masculino , Melanoma/enzimología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Músculo Esquelético/efectos de los fármacos , Trasplante de Neoplasias , Ftalazinas/química , Factores de TiempoRESUMEN
Our recent study has demonstrated that ponalrestat, an aldose reductase inhibitor, activates lipoprotein lipase activity and alleviates B16 melanoma-induced cachexia in mice. In this study, the effect of ponalrestat on murine adenocarcinoma colon26-induced cachexia was investigated in mice. Mice bearing colon26 subcutaneously lost weight and became cachectic, associated with the tumor growth. Although tumor growth was slightly stimulated when tumor bearing mice were treated with ponalrestat: nevertheless, the drug attenuated the reduction in the weight of body mass, epididymal fat, gastrocnemius muscle and carcass induced by colon26, as well as significantly prolonged the survival of the colon26 bearing mice. Ponalrestat inhibited the production of interleukin-1 (IL-1) from human monocytes stimulated by Lipopolysaccharide (LPS) in vitro, and also suppressed LPS-induced increase of IL-1 in the blood in mice. Overall, this study showed that ponalrestat suppresses IL-1 production both in vitro and in vivo, and inhibits the cachectic symptoms induced by colon26 adenocarcinoma in mice, suggesting that ponalrestat has a therapeutic potential for the treatment of cancer cachexia.
Asunto(s)
Adenocarcinoma/complicaciones , Aldehído Reductasa/antagonistas & inhibidores , Caquexia/tratamiento farmacológico , Neoplasias del Colon/complicaciones , Inhibidores Enzimáticos/farmacología , Ftalazinas/farmacología , Animales , Peso Corporal/efectos de los fármacos , Caquexia/etiología , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Epidídimo/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Interleucina-1/antagonistas & inhibidores , Interleucina-1/sangre , Lipopolisacáridos/metabolismo , Linfocitos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Monocitos/metabolismo , Músculo Esquelético/efectos de los fármacos , Trasplante de Neoplasias , Factores de TiempoRESUMEN
FK317, a novel substituted dihydrobenzoxazine, was examined for antitumor effects on multidrug-resistant (MDR) tumor cells in vitro and in vivo. In nude mice, FK317 markedly inhibited the growth of s.c. implanted KB-V1 vinblastine (VLB)-resistant human epidermal carcinoma KB cells, as well as the parent cells (KB-3-1). However, KB-V1 showed much greater resistance to FK317 than to VLB and adriamycin (ADM) in the in vitro study. This resistance was reversed by the addition of verapamil, whereby intracellular accumulation of FK317 in the KB-V1 cells was also decreased. After incubation of FK317 in human and mouse blood, it was shown to be rapidly metabolized to a monodeacetylated form, and slowly metabolized further to a dideacetylated form. With the removal of the acetyl groups from FK317, resistance indexes in KB-V1 and SBC-3/ADM, ADM-resistant human lung carcinoma, decreased. In addition, photolabeling of P-glycoprotein with [3H]azidopine in KB-V1 plasma membrane was completely inhibited by FK317, but not by the deacetylated metabolites. These results indicate that FK317 is metabolized to deacetylated forms, which do not bind to P-glycoprotein and are incorporated into MDR cells, causing cytotoxic effects.
Asunto(s)
Antineoplásicos/toxicidad , Carcinoma de Células Pequeñas/tratamiento farmacológico , Resistencia a Múltiples Medicamentos , Neoplasias Pulmonares/tratamiento farmacológico , Oxazinas/toxicidad , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Marcadores de Afinidad , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Azidas/farmacocinética , Biotransformación , Carcinoma de Células Pequeñas/patología , Supervivencia Celular/efectos de los fármacos , Dihidropiridinas/farmacocinética , Humanos , Células KB , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Desnudos , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/patología , Oxazinas/farmacocinética , Oxazinas/uso terapéutico , Trasplante Heterólogo , Tritio , Vinblastina/toxicidadRESUMEN
PURPOSE: To report the efficacy and safety of fluorescein angiography after oral administration of fluorescein solution in a large number of patients during a period of 8 years. METHODS: A total of 1,787 patients (2,625 eyes) underwent fluorescein angiography after oral administration of sodium fluorescein at Hara Eye Hospital, Utsunomiya, Japan, between January 1989 and March 1997. The ingestible solution was 10 ml of 10% sodium fluorescein, the same material generally used for injection in conventional fluorescein angiography. Retinal photography began 15 minutes after ingestion and continued for 1 hour. The camera and the photography and film processing techniques were the same as those used for conventional fluorescein angiography using injected sodium fluorescein. RESULTS: In 2,554 (97.3%) of 2,625 eyes, photographs adequate for clinical use were obtained. In 1,787 patients, no anaphylactic or other severe adverse effects were observed, and only 31 patients (1.7%) experienced minimal itching, discomfort, or nausea after oral sodium fluorescein intake. For conditions such as central serous chorioretinopathy, retinal vein occlusion, diabetic retinopathy, and cystoid macular edema, sufficient information for clinical use was obtained. CONCLUSIONS: Fluorescein angiography using orally administered sodium fluorescein is generally effective and safe in standard clinical practice.
Asunto(s)
Angiografía con Fluoresceína/métodos , Fluoresceína/administración & dosificación , Colorantes Fluorescentes/administración & dosificación , Enfermedades de la Retina/diagnóstico , Vasos Retinianos/patología , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Fluoresceína/efectos adversos , Colorantes Fluorescentes/efectos adversos , Fondo de Ojo , Humanos , Masculino , Persona de Mediana Edad , Fotograbar , SeguridadRESUMEN
FK317 is a member of a new class of bioreductive agents that exhibit strong cytotoxicity against various human cancer cells. The effect of FK317 was found to be stronger than that of mitomycin C (MMC), adriamycin (ADR) or cisplatin (CDDP). Alkaline elution analysis indicated that FK317 formed interstrand DNA-DNA and DNA-protein cross-links in cells. On the other hand, no DNA single-strand breaks were observed in the cells treated with FK317. In a cell-free system the deacetylated metabolites produced cross-linked DNA under reductive conditions, though FK317 itself did not form DNA-DNA cross-links. In order to elucidate the metabolic activation mechanisms, we established an FK317-resistant subline from human non-small cell lung cancer cells (Lu99) by stepwise and brief exposure (1 h) to FK317. The resistant subline (Lu99/317) showed cross-resistance to MMC and carboquone (CQ), but not to ADR or CDDP. DT-diaphorase, which is one of the activation enzymes of MMC and CQ, was deficient in Lu99/317 cells as determined by enzyme activity assay. However, the levels of NADPH:cytochrome P450 reductase, which is another activation enzyme for MMC and CQ, were comparable in resistant and parent cell lines. Treatment of the cells with dicumarol, an inhibitor of DT-diaphorase, reduced the cytotoxicity of FK317 to Lu99 cells, but not to Lu99/317 cells. These results indicate that deacetylation of FK317 is necessary for its reductive activation, and deacetylated FK317 is reduced by DT-diaphorase to form an active metabolite, which produces DNA-DNA interstrand and DNA-protein cross-links that lead to cell death.
Asunto(s)
Antineoplásicos/farmacología , Oxazinas/farmacología , Animales , División Celular/efectos de los fármacos , Reactivos de Enlaces Cruzados/farmacología , ADN/efectos de los fármacos , Dicumarol/farmacología , Resistencia a Antineoplásicos , Humanos , Leucemia L1210/metabolismo , Oxazinas/química , Células Tumorales CultivadasRESUMEN
PURPOSE: FK973, a substituted dihydrobenzoxazine, is an antitumor antibiotic which has shown high therapeutic efficacy in a phase I study, but its development has been abandoned because of the side effect of vascular leak syndrome (VLS) in the clinical study. This study was performed to investigate whether or not FK317, a new benzmethoxy derivative of FK973, retains the antitumor activity of FK973 without the side effect of VLS. METHODS: VLS was evaluated by the volume of pleural effusion in rats. Cytotoxic activities were determined by a tetrazolium-based colorimetric assay (MTT assay) against murine (B16, P388) and human (HeLa S3, KB) tumor cell lines. Antitumor activities against murine ascitic leukemia (P388, L1210), murine solid tumors (reticulum cell sarcoma M5076, Colon 38 carcinoma) and human xenografts (mammary carcinoma MX-1, lung carcinoma LX-1) were examined. RESULTS: FK973 (1.8 mg/kg) given i.v. to rats induced pleural effusion, one of the elements of VLS, 36 days after the first dosing, but did not 28 days after dosing. This model reflects clinical VLS delayed-type effusion with high protein concentrations. In contrast, FK317 (1.0-3.2 mg/kg) did not induce pleural effusion at all. FK317 had stronger cytotoxic effects against in vitro cultured B16, P388, HeLa S3 and KB tumor cell lines, and in in vivo experiments, FK317 showed equivalent antitumor activity against P388, M5076 and MX-1, and more potent antitumor activity against L1210, Colon 38 and LX-1 compared with FK973. CONCLUSION: These results suggest that FK317 retains the antitumor activity of FK973 and does not induce VLS, and FK317 is a drug with high clinical potential for treating tumors in humans.
Asunto(s)
Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Síndrome de Fuga Capilar/inducido químicamente , Neoplasias Experimentales/tratamiento farmacológico , Oxazinas/efectos adversos , Oxazinas/farmacología , Animales , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Masculino , Ratones , Ratones Endogámicos , Mitomicina/efectos adversos , Mitomicina/farmacología , Derrame Pleural/inducido químicamente , Ratas , Ratas Sprague-Dawley , Células Tumorales CultivadasRESUMEN
Cancer cachexia, characterized by weight loss and progressive tissue wasting, has been postulated to be mediated by cytokines. In this study the effect of FR143430, (2-(4-fluorophenyl)-4, 5, 6, 7-tetrahydro-3-(4-pyridyl)pyrazolo[1, 5-a]pyrimidine monohydrochloride), an inhibitor of Interleukin-1 and Tumor necrosis factor-a (TNF- a), on adenocarcinoma colon26-induced cachexia was investigated in mice. Tumor growth was not affected. Nevertheless, treatment with FR143430 (0.1 to lmg) into the tumor resulted in the attenuation of the reduction in body weight, food intake, epididymal fat and carcass weight, the decrease in the circulating levels of triglyceride and glucose, and the increase in the circulating levels of total cholesterol, non esterified free fatty acid (NEFA) and total protein, which were induced by the presence of the tumor. However, oral treatment with FR143430 failed to show an inhibitory effect on cachexia induction. Overall, this study demonstrated that the cachexia induced by colon26 was alleviated by the injection of FR143430 into the tumor in sufficient quantity, without any effect on tumor growth, suggesting the potential utility of cytokine suppressive agents e for the treatment of cancer cachexia.
Asunto(s)
Caquexia/tratamiento farmacológico , Citocinas/antagonistas & inhibidores , Neoplasias Experimentales/tratamiento farmacológico , Pirazoles/farmacología , Pirimidinas/farmacología , Animales , Caquexia/sangre , Células Cultivadas , Neoplasias del Colon/sangre , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Humanos , Leucocitos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Monocitos/efectos de los fármacos , Neoplasias Experimentales/sangre , Neoplasias Experimentales/patologíaRESUMEN
The effects of FK317 (11-acetyl-8-carbamoyloxymethyl-4-formyl-6- methoxy-14-oxa-1,11-diazatetracyclo[7.4.1.0(2, 7). 0(10, 2] tetradeca-2,4,6-trien-9-yl acetate), a novel anti-cancer agent, on murine adenocarcinoma colon26- and human lung carcinoma LX-1-induced cachexia were investigated in mice. Mice bearing colon26 or LX-1 s.c. lost weight and became cachectic, associated with tumor growth. FK317 and mitomycin C (MMC) inhibited the growth of both tumors. FK317 ameliorated the weight loss induced by the presence of colon26 or LX-1, while MMC enhanced it. An attenuation of the reduction in the weights of epididymal fat, gastrocnemius muscle and carcass was observed in FK317-treated tumor-bearing mice in both cachexia models, but not in MMC-treated mice. The decreases in the circulating levels of triglyceride, glucose and non-esterified fatty acid, which were induced by the presence of colon26, was partially inhibited by treatment with FK317. Overall, this study revealed that FK317 is a potent anti-cancer drug with anti-cachectic activity, suggesting that FK317 has potential utility for the treatment of cancer.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Caquexia/prevención & control , Carcinoma/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Oxazinas/uso terapéutico , Adenocarcinoma/sangre , Adenocarcinoma/complicaciones , Adenocarcinoma/patología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/patología , Animales , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Glucemia/análisis , Peso Corporal/efectos de los fármacos , Caquexia/sangre , Caquexia/etiología , Caquexia/patología , Carcinoma/sangre , Carcinoma/complicaciones , Carcinoma/patología , Neoplasias del Colon/sangre , Neoplasias del Colon/complicaciones , Neoplasias del Colon/patología , Ensayos de Selección de Medicamentos Antitumorales , Epidídimo/efectos de los fármacos , Ácidos Grasos no Esterificados/sangre , Femenino , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mitomicina/farmacología , Mitomicina/uso terapéutico , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Tamaño de los Órganos/efectos de los fármacos , Oxazinas/farmacología , Triglicéridos/sangreRESUMEN
The antitumor effects of FK317, a novel substituted dihydrobenzoxazine, were evaluated using human tumor xenografts (small cell lung cancer, non-small cell lung cancer, stomach cancer, colon cancer, pancreatic cancer, breast cancer, cervical cancer and ovarian cancer). Tumor growth-inhibitory effects and the effective dose-range of FK317 were much stronger and broader, respectively, than those of reference drugs such as mitomycin C, adriamycin, cisplatin, taxol and irinotecan. Furthermore, the body weight decrease and myelosuppression in FK317-treated mice were less than in the animals given any of the reference drugs. To explain this tumor selectivity, the distribution of FK317 was investigated after dosing tumor-bearing mice with the 14C-labelled compound. The concentration of FK317 in tumor tissues was relatively low, and long tumor retention was not observed. However, thin-layer chromatographic separation revealed that the radioactivity in the tumor resided mainly in strongly cytotoxic metabolites, while that in other tissues resided mainly in non-cytotoxic metabolites. These results suggest that FK317 shows strong antitumor activity without side effects, and one reason for this is its specific metabolite pattern. FK317 is now undergoing phase I clinical trials.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Experimentales/tratamiento farmacológico , Oxazinas/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidad , Biotransformación , Peso Corporal/efectos de los fármacos , Carcinoma de Células Grandes/tratamiento farmacológico , Carcinoma de Células Grandes/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Cisplatino/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Doxorrubicina/uso terapéutico , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Células HeLa/efectos de los fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mitomicina/uso terapéutico , Trasplante de Neoplasias , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Oxazinas/farmacocinética , Oxazinas/toxicidad , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Distribución Tisular , Trasplante Heterólogo , Células Tumorales Cultivadas/trasplante , Ensayo de Tumor de Célula MadreRESUMEN
FK143 (4-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]-1H-indol-1-yl] - butyric acid) is a new non-steroidal inhibitor of steroid 5 alpha-reductase (5 alpha-reductase). The effects of FK143 on prostate size and histopathology of mature male beagle dogs were investigated and compared with those of finasteride (a steroidal 5 alpha-reductase inhibitor), and allylestrenol and chlormadinone acetate (CMA) (androgen receptor antagonists). FK143 was orally administered to the dogs daily for 12 weeks. At doses of 10 and 32 mg/kg, FK143 significantly reduced prostate volume to about 60% of the initial value, and dogs treated with FK143 showed a dose-dependent glandular epithelial atrophy in the prostate. FK143 showed no abnormal changes in organ weights and histopathology of the adrenal, testis, pituitary and liver. The degree of prostate reduction in the dogs treated with FK143 (10 and 32 mg/kg) was almost the same as that by finasteride (1.0 mg/kg) and smaller than that by allylestrenol (10 mg/kg) or CMA (10 mg/kg). However, allylestrenol increased liver weights, and CMA increased liver and reduced adrenal weights. These results demonstrate that FK143 can decrease the volume of the dog prostate without any influence on other organs, and they suggest that FK143 is a good candidate for the treatment for benign prostatic hyperplasia.
Asunto(s)
Inhibidores de 5-alfa-Reductasa , Indoles/farmacología , Fenilbutiratos/farmacología , Próstata/efectos de los fármacos , Alilestrenol/farmacología , Antagonistas de Receptores Androgénicos , Animales , Acetato de Clormadinona/farmacología , Perros , Finasterida/farmacología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Congéneres de la Progesterona/farmacología , Próstata/citología , Próstata/diagnóstico por imagen , Unión Proteica/efectos de los fármacos , Receptores Androgénicos/metabolismo , UltrasonografíaRESUMEN
FK143 is a nonsteroidal new inhibitor of steroid 5 alpha-reductase, an enzyme which converts testosterone into 5 alpha-dihydrotestosterone (DHT). We studied in vivo effects of FK143 on rat and dog prostates. FK143 was orally administered to mature male rats for 14 days. At doses above 1 mg/kg, FK143 significantly reduced the wet weights of the ventral prostate and seminal vesicle, but showed no effects on those of the epididymis, testis, and adrenal. Growth of ventral prostate and seminal vesicle was induced by the subcutaneous injection of testosterone propionate (TP) in the castrated young rats and was reduced by FK143 administration at doses above 3.2 mg/kg, while growth induced by 5 alpha-dihydrotestosterone propionate (DHTP) was not affected. FK143 had no binding affinity for the rat androgen receptor. FK143 showed neither estrogenic and antiestrogenic effects on the rat uterus nor androgenic effect on the rat prostate. Concentration of testosterone and DHT in the rat and dog prostates were measured by GC-MS, and administration of 10 mg/kg of FK143 significantly reduced the intraprostatic concentration of DHT. These results indicate that FK143 reduced the prostate growth by inhibiting 5 alpha-reductase activities in the prostates.
Asunto(s)
Inhibidores de 5-alfa-Reductasa , Indoles/farmacología , Fenilbutiratos/farmacología , Próstata/efectos de los fármacos , Administración Oral , Factores de Edad , Andrógenos/análisis , Animales , Citosol , Dihidrotestosterona/análisis , Perros , Femenino , Masculino , Orquiectomía , Tamaño de los Órganos/efectos de los fármacos , Próstata/química , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Receptores Androgénicos/análisis , Vesículas Seminales/efectos de los fármacos , Factores Sexuales , Testosterona/análisis , Útero/efectos de los fármacosRESUMEN
Steroid 5 alpha-reductase is an enzyme which converts testosterone into 5 alpha-dihydrotestosterone (DHT) and is implicated in the pathogenesis of benign prostatic hyperplasia (BPH) in men. We studied in vitro effects of FK143, a nonsteroidal new compound, on 5 alpha-reductase in human and animal prostates. Prostates were obtained from Wistar rats, Beagle dogs, and Cynomolgus monkeys as well as prostatic tissue from BPH patients obtained by the prostatectomy. Nuclear membrane fraction of prostates showed pH dependent 5 alpha-reductase activities, and inhibitory effects of drugs were assayed at pH 6.5. FK143 inhibited human prostatic 5 alpha-reductase in a dose-dependent manner with an IC50 of 1.9 nM and also inhibited animal 5 alpha-reductases with similar IC50 values. FK143 inhibited human and rat 5 alpha-reductases in a noncompetitive fashion while finasteride, a steroidal 5 alpha-reductase inhibitor, showed competitive inhibition. The affinities of FK143 for the human 5 alpha-reductase is constant at pH 5 and 6.5. No inhibitory effects were shown to other oxidoreductases. These results indicate that FK143 is a new type of potent and selective 5 alpha-reductase inhibitor.
Asunto(s)
Inhibidores de 5-alfa-Reductasa , Indoles/farmacología , Fenilbutiratos/farmacología , Próstata/enzimología , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/aislamiento & purificación , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismo , Animales , Perros , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Finasterida/farmacología , Humanos , Concentración de Iones de Hidrógeno , Macaca fascicularis , Masculino , Membrana Nuclear/enzimología , Ratas , Ratas Wistar , Especificidad de la Especie , Testosterona/farmacologíaRESUMEN
The first enzyme in the formation of GDP-L-fucose from GDP-D-mannose, which forms a GDP-4-keto sugar intermediate, was purified to homogeneity from cell extracts of Klebsiella pneumoniae. During purification, the enzyme was found to be highly activated by NADP. It was proven that the pyridine nucleotide coenzyme of the enzyme was NADP, not NAD, which differs from previously accepted information. NAD had no effect on enzyme activity. The product of the enzyme reaction with NADP as coenzyme was separated from other nucleotides by high-performance liquid chromatography, and using ion spray liquid chromatography/mass spectrometry the mass was determined for the first time, as 587, which is same as the calculated mass of GDP-4-keto-6-deoxy-D-mannose.
Asunto(s)
Deshidrogenasas de Carbohidratos/aislamiento & purificación , Deshidrogenasas de Carbohidratos/metabolismo , Guanosina Difosfato Manosa/metabolismo , Klebsiella pneumoniae/enzimología , NADP/metabolismo , Cromatografía DEAE-Celulosa , Cromatografía en Gel , Cromatografía Líquida de Alta Presión , Guanosina Difosfato Manosa/análogos & derivados , Guanosina Difosfato Manosa/análisis , Cinética , Espectrometría de Masas , NAD/metabolismo , Especificidad por SustratoRESUMEN
To evaluate the number and function of suppressor T cells in children with minimal change nephrotic syndrome (MCNS), we performed an inhibition test of rosette formation and measured leukocyte procoagulant activity. The number of histamine H2 receptor-bearing T lymphocytes (histamine H2 R+ lymphocytes) was markedly decreased at the onset of MCNS but gradually increased and was normalized following steroid therapy. The production of leukocyte procoagulant activity by normal T lymphocytes was abolished by incubation with patient's lymphocytes. However, pretreatment of the normal T lymphocytes with cimetidine markedly decreased the suppression. The results suggest an abnormality in the histamine H2 receptors on the patient's suppressor T lymphocytes.