RESUMEN
At present curative resection is the only radical treatment for gastric cancer, although recently developed combination chemotherapy shows increased activity in treating locally advanced and metastatic disease. Among several combination regimens, those based on biochemical modulation, such as sequential methotrexate/5-fluorouracil or low-dose CDDP/5-fluorouracil, are thought to provide increased efficacy with decreasing adverse reactions in unresectable gastric cancer. Therefore, a prospective randomized clinical trial comparing the prognosis of patients receiving adjuvant multi-agent chemotherapy with those treated only surgically should be pursued for estimation of the clinical benefit of these agents.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factores Inmunológicos/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Antineoplásicos Fitogénicos/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Fluorouracilo/administración & dosificación , Humanos , Irinotecán , Metotrexato/administración & dosificación , Neoplasias Gástricas/cirugíaRESUMEN
The effects of diltiazem and phosphoramidon on sudden death induced by endothelin (ET)-1 and by big ET-1 were compared in rodents. Diltiazem (2 mg/kg, i.v.) remarkably diminished the lethal toxicity of ET-1 with a reduction in the extent of the rise in plasma immunoreactive ET-1-like activity (IR-ET-1), tissue IR-ET-1 accumulation in the heart and the rise in plasma potassium concentration. In big ET-1-induced lethality, diltiazem only slightly prolonged the latency and did not reduce the mortality. Although diltiazem moderately inhibited the rise in plasma IR-ET-1 and potassium concentration in these mice, it did not affect the accumulation of IR-ET-1 in the heart, lung or kidney. Phosphoramidon (2 mg/kg, i.v.) decreased the lethality of big ET-1 with the decrement in elevation of IR-ET-1 in the heart, lung and plasma as well as with the decrease in plasma potassium concentration, but it failed to improve any parameters in ET-1-induced lethality. In anesthetized rats, ET-1 (5 nmol/kg, i.v.) elevated ST-segment of electromyocardiograms, and diltiazem (2 mg/kg, i.v.) significantly reversed this change. Big ET-1 (25 nmol/kg, i.v.) also induced the ST-segment elevation, which was significantly inhibited by phosphoramidon but not by diltiazem. These findings suggest that accumulation of ET-1 in the heart, which may lead to lethal cardiac ischemia, is an important factor in the lethality of ET-1, while additional factors (such as hemoconcentration and bronchoconstriction) may be involved in big ET-1-induced lethality.
Asunto(s)
Muerte Súbita Cardíaca , Endotelinas/toxicidad , Precursores de Proteínas/toxicidad , Anestesia , Animales , Diltiazem/farmacología , Electrocardiografía , Endotelina-1 , Endotelinas/antagonistas & inhibidores , Endotelinas/metabolismo , Glicopéptidos/farmacología , Riñón/metabolismo , Pulmón/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Isquemia Miocárdica/inducido químicamente , Miocardio/metabolismo , Potasio/sangre , Inhibidores de Proteasas/farmacología , Precursores de Proteínas/antagonistas & inhibidores , Precursores de Proteínas/metabolismoRESUMEN
We investigated the profiles of sudden death and hemoconcentration induced by endothelin-1 (ET-1) and big endothelin-1 (big ET-1) in mice using various compounds as pharmacological tools. In ET-1-induced sudden death (5 nmol/kg, i.v.), pretreatment with the Ca(2+)-channel blockers, diltiazem, nifedipine or verapamil at a dose of 2 mg/kg, i.v. significantly inhibited the mortality and prolonged the latency to death. These Ca(2+)-channel blockers, however, failed to inhibit the rise in hematocrit (Ht), namely hemoconcentration, induced by ET-1 (2.5 nmol/kg). A beta-adrenoceptor agonist, isoproterenol (1 mg/kg) tended to prolong the latency, whereas, a beta-adrenoceptor blocker, propranolol (2 mg/kg), and an alpha- and beta-adrenoceptor blocker, labetalol (5 mg/kg), aggravated the sudden death. Esculetin (10 mg/kg) and fenbufen (10 mg/kg), which are enzyme inhibitors in the arachidonate cascade, prevented only the hemoconcentration. Anti-arrhythmic drugs, lidocaine (1 mg/kg) and disopyramide (20 mg/kg) did not improve any parameters. Big ET-1 also caused sudden death (20 and 25 nmol/kg, i.v.) and hemoconcentration (10 nmol/kg, i.v.). Of several proteinase inhibitors, only a metalloproteinase inhibitor, phosphoramidon (2 mg/kg i.v.), prevented the sudden death and the hemoconcentration induced by big ET-1 but not by ET-1. Ca(2+)-channel blockers exerted their protective effects only when a lower dose of big ET-1 was employed. These results indicate that the sudden death caused by both peptide is mainly due to myocardial ischemia and respiratory disorder, and that hemoconcentration caused by them is due to their vasoconstrictor action but to their effects on the vascular permeability via secondary endogenous factors.
Asunto(s)
Muerte Súbita/etiología , Endotelinas/toxicidad , Precursores de Proteínas/toxicidad , Antagonistas Adrenérgicos alfa/farmacología , Agonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Aorta/enzimología , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Bloqueadores de los Canales de Calcio/farmacología , Bovinos , Endotelina-1 , Enzimas Convertidoras de Endotelina , Endotelinas/antagonistas & inhibidores , Hematócrito , Humanos , Masculino , Metaloendopeptidasas/antagonistas & inhibidores , Ratones , Ratones Endogámicos ICR , Inhibidores de Proteasas/farmacología , Precursores de Proteínas/antagonistas & inhibidoresRESUMEN
New substituted 1,8-naphthyridin-2(1H)-ones have been found to exhibit highly selective phosphodiesterase (PDE) IV inhibition. These compounds inhibited polymorphonuclear leukocyte activation induced by N-formylmethionyl-leucyl-phenylalanine and caused relaxation of isolated guinea pig trachea precontracted by histamine or leukotriene D4. In anesthetized guinea pigs, presensitized with the antigen, these compounds also alleviated airway constriction induced by the antigen. Since these compounds differ in their chemical structure compared with theophylline and other PDE IV inhibitors so far reported and some of them have been shown to be well tolerated in acute toxicity studies, they will provide a new tool for investigating the possible relationship between PDE IV inhibition and anti-asthmatic activity.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas , Broncoconstricción/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Naftiridinas/farmacología , Neutrófilos/efectos de los fármacos , Inhibidores de Fosfodiesterasa/toxicidad , Hidrolasas Diéster Fosfóricas/metabolismo , Animales , Antígenos/inmunología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Cobayas , Técnicas In Vitro , Isoenzimas/antagonistas & inhibidores , Masculino , Relajación Muscular/efectos de los fármacos , Naftiridinas/química , Naftiridinas/toxicidad , Neutrófilos/fisiología , Tráquea/efectos de los fármacosRESUMEN
The effects of metal chelators on endothelin (ET)-converting enzyme (ECE) activity in vivo were examined. Three compounds, (2,3-dimercapto-1-propanol (DMP), toluene-3,4-dithiol (TDT) and 8-mercaptoquinoline (8-MQ)), which inhibited ECE in in vitro studies, exhibited inhibitory activity towards big ET-1-induced sudden death in mice, while EDTA did not. Similar results were obtained in big ET-1-induced hypertension. Big ET-1-induced hemoconcentration was inhibited by pretreatment with 8-MQ or EDTA but not with DMP or TDT. The elevation of immunoreactive ET-1 (IR-ET-1) in plasma after administration of big ET-1 was inhibited by pretreatment with the three compounds but not by EDTA. On the other hand, no chelator inhibited the elevation of IR-ET-1 in lung tissue after injection of big ET-1. Taking into consideration the in vitro results, more selective chelating activity of the compounds towards Zn2+ rather than Ca2+ and Mg2+ may contribute to the inhibition of big ET-1-induced responses in vivo. The ET-1 formation involved in big ET-1-induced hemoconcentration may have different physiological characteristics from that involved in big ET-1-induced sudden death or hypertension.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Quelantes/farmacología , Músculo Liso Vascular/efectos de los fármacos , Animales , Aorta Torácica/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Muerte Súbita , Dimercaprol/farmacología , Ácido Edético/farmacología , Endotelina-1 , Enzimas Convertidoras de Endotelina , Endotelinas/administración & dosificación , Endotelinas/sangre , Endotelinas/metabolismo , Endotelinas/toxicidad , Glicopéptidos/farmacología , Hematócrito , Pulmón/metabolismo , Masculino , Metaloendopeptidasas , Ratones , Ratones Endogámicos ICR , Contracción Muscular/efectos de los fármacos , Precursores de Proteínas/administración & dosificación , Precursores de Proteínas/toxicidad , Quinolinas/administración & dosificación , Quinolinas/farmacología , Ratas , Ratas Sprague-Dawley , Tolueno/análogos & derivados , Tolueno/farmacologíaRESUMEN
The effects of various metal chelators on endothelin (ET)-converting enzyme (ECE) activity were examined in vitro. Three chelators, 2,3-dimercapto-1-propanol (DMP), toluene-3,4-dithiol (TDT) and 8-mercaptoquinoline (8-MQ), were found to dose-dependently inhibit ECE activity, but this inhibition was much weaker compared with EDTA. In the presence of Zn2+, the inhibitory activity of all these compounds, including EDTA, was abolished. The addition of Ca2+ and Mg2+ markedly attenuated the inhibitory activity of EDTA, but the other three chelators were still able to inhibit ECE. ECE, once inactivated by EDTA or 8-MQ, was reactivated by the addition of divalent cations such as Zn2+ and Mn2+. These compounds also inhibited angiotensin-converting enzyme activity in a manner similar to the inhibition exhibited towards ECE. Chelate-titration indicated that DMP, TDT and 8-MQ chelate Zn2+ but not Ca2+ and Mg2+. These results suggest that the ECE inhibition exhibited by these compounds is mainly attributable to their chelating activities. The metal-selective chelating activity by DMP, TDT and 8-MQ may contribute to the retention of ECE inhibition in the presence of Ca2+ and Mg2+.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Quelantes/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina , Animales , Calcio/farmacología , Bovinos , Línea Celular , Relación Dosis-Respuesta a Droga , Ácido Edético/farmacología , Enzimas Convertidoras de Endotelina , Endotelio Vascular/citología , Endotelio Vascular/enzimología , Magnesio/farmacología , Metaloendopeptidasas , Quinolinas/farmacología , Tolueno/análogos & derivados , Tolueno/farmacologíaRESUMEN
1. The profile of haemoconcentration induced by big endothelin-1(big ET-1), a precursor of endothelin-1 (ET-1), was compared with that induced by endothelin-1 in mice. 2. ET-1(1.5 nmol kg-1, i.v.) increased haematocrit in mice, which reached a maximum at 5 min and then returned to the control value within 30 min after the administration, this occurred at the same time as changes in the plasma immunoreactive endothelin-1 and rat atrial natriuretic peptide (rANP)-like activities (IR-ET-1 and IR-rANP, respectively). 3. Big ET-1(2.5-15 nmol kg-1, i.v.) also caused a significant and dose-dependent increase in haematocrit, that lasted over 3 h although elevated plasma IR-ET-1 and IR-rANP had almost been restored to the initial levels within 10 min after big ET-1 injection. 4. A metalloproteinase inhibitor, phosphoramidon (10 mg kg-1, i.v.), which inhibits the activity of endothelin converting enzyme (ECE), delayed the onset of big ET-1-induced haemoconcentration, but failed to alter the maximal value and the duration of the haemoconcentration. 5. Pretreatment with phosphoramidon (10 mg kg-1, i.v.) did not affect the big ET-1-induced change in plasma IR-ET-1, while significant delay of the disappearance of plasma IR-rANP and significant suppression of a sustained increase in tissue IR-ET-1 were observed. 6. These results suggest that ET-1, not in plasma but in tissue, plays an important role in the pathogenesis of big ET-1-induced long-lasting haemoconcentration, in which unknown factors besides rANP are involved.
Asunto(s)
Endotelinas/farmacología , Hematócrito , Precursores de Proteínas/farmacología , Animales , Factor Natriurético Atrial/metabolismo , Factor Natriurético Atrial/farmacología , Relación Dosis-Respuesta a Droga , Endotelina-1 , Endotelinas/sangre , Glicopéptidos/farmacología , Masculino , Ratones , Ratones Endogámicos ICRRESUMEN
Aspergillomarasmine-A and -B (AM-A and -B), which were isolated from the cultured broth of an unidentified fungus N877, showed apparent inhibition against endothelin-converting enzyme (ECE) from bovine endothelial cells as measured by the formation of endothelin-1 (ET-1) converted from big endothelin-1 (bET-1), with IC50 values of 3.4 and 2.5 microM for AM-A and -B, respectively. EDTA also inhibited ECE (IC50 = 1.1 microM), but the inhibitions by AM-A, AM-B and EDTA were each abolished by the addition of 10 microM Zn2+ to the reaction mixture. In mice, AM-A and -B dose-dependently (10-50 mg/kg, i.v.) caused significant prolongation of the latency to sudden death induced by i.v. bET-1 (25 nmol/kg), but not that by ET-1 (5 nmol/kg), accompanied by a decrease in plasma immunoreactive ET-1 formation, while EDTA (24 mg/kg) failed to do so. In mice, the LD50 value of AM-A was calculated to be 159.8 mg/kg, i.v., which was much larger than that of EDTA (28.5 mg/kg, i.v.), indicating the low toxicity of AM-A. AM-A (30 mg/kg, i.v.) also suppressed bET-1-induced hemoconcentration and hypertension in mice and rats, respectively. These findings suggest that although ECE inhibition by AM-A was mainly attributable to its chelating activity, it showed apparent in vivo activities due to ECE inhibition with low toxicity.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico/análogos & derivados , Endotelio Vascular/efectos de los fármacos , Animales , Aorta/efectos de los fármacos , Ácido Aspártico/farmacología , Ácido Aspártico/toxicidad , Bovinos , Ácido Edético/farmacología , Enzimas Convertidoras de Endotelina , Endotelinas/sangre , Endotelinas/efectos de los fármacos , Endotelinas/farmacología , Glicopéptidos/farmacología , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Técnicas In Vitro , Dosificación Letal Mediana , Masculino , Metaloendopeptidasas/antagonistas & inhibidores , Ratones , Ratones Endogámicos ICR , Ratas , Ratas Sprague-DawleyRESUMEN
Protein phosphorylation by okadaic acid and 12-O-tetradecanoylphorbol-13-acetate (TPA) was examined using quiescent cultures of BALB/MK-2, a cell line derived from mouse epidermal keratinocytes. Treatment with okadaic acid caused rapid phosphorylation of five proteins with molecular masses of 65, 55, 50, 28 and 15 kDa (p65, p55, p50, p28, p15, respectively) while TPA caused rapid phosphorylation of five proteins with molecular masses of 80, 70, 40, 34 and 28 kDa (p80, p70, p40, p34, p28, respectively). In the present study, we examined p28, a common target protein of okadaic acid and TPA. The phosphorylation of p28 increased depending on time of exposure and doses of okadaic acid and TPA. Combined treatment with okadaic acid and TPA resulted in an additive effect. Its position on two-dimensional gel electrophoresis suggested that p28 is the 28-kDa heat-shock protein (HSP28). This possibility was confirmed by migration of p28 with HSP28 and comparative peptide mapping of the two proteins. The phosphoamino-acid residue of phosphorylated HSP28 was serine. In two-dimensional tryptic peptide maps, the same peptides were phosphorylated after treatment with both okadaic acid and TPA.
Asunto(s)
Carcinógenos/farmacología , Éteres Cíclicos/farmacología , Proteínas de Choque Térmico/metabolismo , Queratinocitos/metabolismo , Acetato de Tetradecanoilforbol/farmacología , Animales , Línea Celular , Proteínas de Choque Térmico/química , Humanos , Ratones , Ácido Ocadaico , Mapeo Peptídico , Fosforilación , Proteína Quinasa C/metabolismoRESUMEN
When 58 minute gastric cancers less than 5 mm in diameter from 55 patients were classified into 22 of the single group (minute gastric cancer alone) and 36 of the multiple group (associated with other large gastric cancers), the preoperative correct diagnostic rate by x-ray was 22.7% and 11.1% in the single group and in the multiple group, respectively, with a total rate of 15.5%. The diagnostic rate by endoscopy, aided by endoscopic biopsy, was 95.5%, 13.9%, and 44.8%, respectively. Therefore, it appears that endoscopy and endoscopic biopsy are most efficient diagnostic tools for the detection of such minute gastric cancers. Since the detection of the depressed type (IIc) of minute gastric cancers is considered most significant because of their frequent submucosal invasion, their characteristic endoscopic findings are emphasized: (1) irregular and polygonal shape, (2) distinct depression, (3) clear demarcation, (4) nodular margins, and (5) moth-eaten appearance and abrupt thinning of the mucosal folds.
Asunto(s)
Endoscopía , Neoplasias Primarias Múltiples , Neoplasias Gástricas/patología , Biopsia , Femenino , Gastroscopía , Humanos , Japón , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Radiografía , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/cirugíaRESUMEN
Minute gastric cancers with maximum dimensions of less than 5 mm were studied clinicopathologically. There were 49 intramucosal cancers among 46 patients and nine submucosal cancers among nine patients. No lymph node metastasis was found. Macroscopically, eight (13.8%) were evaluated, 12 (20.7%) were flat, and 38 (65.5%) were depressed. Most submucosal cancers were of the depressed type (8/9, 88.9%). Classification of cancers according to association with other large cancers into single group (22 cases) and multiple group (33 cases) revealed that (1) the majority of the minute gastric cancers (20/22, 90.9%) in the single group were the depressed type and (2) submucosal cancers in the single group were 8/22, accounting for 36.4%, a much higher incidence as compared with 1/36 (2.9%) in the multiple group. These facts indicate that gastric cancers should be detected when they are about 5 mm in maximum dimension and before they invade beyond the submucosal layer, especially in single and depressed type.