RESUMEN
PURPOSE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity of twice-weekly gemcitabine and concurrent thoracic radiation in patients with Stage IIIa/IIIb non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Seventeen patients with histologically confirmed Stage IIIa and IIIb NSCLC were studied. Gemcitabine was administered via a 30-min i.v. infusion twice weekly for 6 weeks concurrent with 60 Gy of thoracic radiation. Gemcitabine, starting at a twice-weekly dose of 10 mg/m2 (20 mg/m2/week), was escalated in 10-15 mg/m2 increments in successive cohorts of 3 to 6 patients until dose-limiting toxicity was observed. RESULTS: Of the 17 patients entered, 16 were evaluable for toxicity. The dose-limiting toxicity at 50 mg/m2 given twice weekly (100 mg/m2/week) was Grade 3 pneumonitis observed in 1 patient, Grade 3 pulmonary fibrosis in a second patient, and Grade 4 esophagitis observed in two additional patients. Twice-weekly gemcitabine at a dose of 35 mg/m2 was determined to be the MTD. The overall response rate for the 16 evaluable patients was 88%. The median survival for the entire group is 16.0 months. CONCLUSIONS: The MTD of twice-weekly gemcitabine is 35 mg/m2 (70 mg/m2/week) given with thoracic radiation. A Phase II study within the Cancer and Leukemia Group B to ascertain the potential efficacy of this treatment regimen is in development.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/terapia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Neoplasias Pulmonares/terapia , Tórax/efectos de la radiación , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , GemcitabinaRESUMEN
PURPOSE: NF-kappaB is activated by tumor necrosis factor, certain chemotherapeutic agents, and ionizing radiation, leading to inhibition of apoptosis. NF-kappaB activation is regulated by phosphorylation of IkappaB inhibitor molecules that are subsequently targeted for degradation by the ubiquitin-proteasome pathway. PS-341 is a specific and selective inhibitor of the proteasome that inhibits NF-kappaB activation and enhances cytotoxic effects of chemotherapy in vitro and in vivo. The objective of this study was to determine if proteasome inhibition leads to enhanced radiation sensitivity. METHODS AND MATERIALS: Inhibition of NF-kappaB activation in colorectal cancer cells was performed by treatment of LOVO cells with PS-341 or infection with an adenovirus encoding IkappaB super-repressor, a selective NF-kappaB inhibitor. Cells were irradiated at 0, 2, 4, 6, 8, and 10 Gy with or without inhibition of NF-kappaB. NF-kappaB activation was determined by electrophoretic mobility gel shift assay, and apoptosis was evaluated using the TUNEL assay. Growth and clonogenic survival data were obtained to assess effects of treatment on radiosensitization. In vitro results were tested in vivo using a LOVO xenograft model. RESULTS: NF-kappaB activation was induced by radiation and inhibited by pretreatment with either PS-341 or IkappaBalpha super-repressor in all cell lines. Inhibition of radiation-induced NF-kappaB activation resulted in increased apoptosis and decreased cell growth and clonogenic survival. A 7-41% increase in radiosensitivity was observed for cells treated with PS-341 or IkappaBalpha. An 84% reduction in initial tumor volume was obtained in LOVO xenografts receiving radiation and PS-341. CONCLUSIONS: Inhibition of NF-kappaB activation increases radiation-induced apoptosis and enhances radiosensitivity in colorectal cancer cells in vitro and in vivo. Results are encouraging for the use of PS-341 as a radiosensitizing agent in the treatment of colorectal cancer.
Asunto(s)
Ácidos Borónicos/farmacología , Proteínas I-kappa B , Complejos Multienzimáticos/antagonistas & inhibidores , FN-kappa B/fisiología , Inhibidores de Proteasas/farmacología , Pirazinas/farmacología , Tolerancia a Radiación/fisiología , Fármacos Sensibilizantes a Radiaciones/farmacología , Adenoviridae/genética , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Bortezomib , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/radioterapia , Cisteína Endopeptidasas , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/fisiología , Femenino , Humanos , Ratones , Ratones Desnudos , Inhibidor NF-kappaB alfa , FN-kappa B/antagonistas & inhibidores , Complejo de la Endopetidasa Proteasomal , Tolerancia a Radiación/efectos de los fármacos , Proteínas Represoras/genética , Proteínas Represoras/fisiología , Transducción Genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The intent of this feasibility study was to evaluate the use of intra-operative electron radiotherapy (IOERT), after transurethral resection (TUR), combined with external beam radiation with concurrent chemotherapy for the conservative treatment of infiltrating bladder cancer. From November 1988 to June 1998, 27 patients with histologically proven non-metastatic infiltrating bladder cancer were included in this protocol. The treatment consisted of: TUR, external beam irradiation (x18 MV:48 Grays (Gy)/24 fractions/5 weeks), with concurrent chemotherapy (cisplatin 30 mg/day for 3 days-two cycles during irradiation), followed by control cystoscopy and cystotomy with IOERT (e 9 MeV:15 Gy). 14 patients received two cycles of neoadjuvant methotrexate, vinblastine and cisplatin (MVC) and folinic acid chemotherapy. Patients were evaluated for toxicity, local control and survival. The 5-year overall and cystectomy-free survival rates were 53.3% +/-11.1% and 48.1%+/-11.4%, respectively. 4 patients developed infiltrating intravesicular recurrence (3 were treated by salvage cystectomy), and an additional patient developed a superficial recurrence. 2 patients subsequently developed regional recurrence in pelvic nodes and 10 patients were found to have distant metastases. The protocol was found to be feasible and associated with acceptable toxicity. Early and late toxicities consisted of 3 cases of bladder mucosal necrosis or ureteral stenosis which resolved with medical management. These preliminary results indicate that IOERT combined with TUR and neoadjuvant external beam radiation with concurrent chemotherapy is feasible. It could be considered as an alternative therapy for infiltrating carcinoma of the bladder, especially in patients unfit for radical surgery, and is well adapted to treat lesions of the fixed portion of the bladder.
Asunto(s)
Carcinoma Intraductal no Infiltrante/radioterapia , Electrones/uso terapéutico , Neoplasias de la Vejiga Urinaria/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Intraductal no Infiltrante/cirugía , Supervivencia sin Enfermedad , Estudios de Factibilidad , Femenino , Humanos , Cuidados Intraoperatorios/métodos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Proyectos Piloto , Radioterapia/efectos adversos , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
Metalloporphyrins, including heme and others that inhibit heme oxygenase, are agents with expanding therapeutic potential. Recent results from our laboratory showed that a combination of heme and zinc-mesoporphyrin was remarkably effective in ameliorating biochemical features of acute porphyria. The aim of this study was to assess plasma clearance, tissue distribution and persistence, stability, toxicology and metabolic effects of zinc-mesoporphyrin, after its i.v. administration to rats. After administration of 15 mumol/kg b.wt. of zinc-mesoporphyrin (bound to serum albumin in a 1:1 molar ratio) the metalloporphyrin was rapidly cleared from plasma (half-life 3.6 h) with uptake primarily into liver and spleen, considerably less into the kidney and none detectable into the heart or brain. Hepatic heme oxygenase activity was undetectable for 4 days and less than 50% of control 1 week later. Inhibition of splenic heme oxygenase activity was also substantial but less marked than in the liver. No mortality was observed in any of the treated animals, and there was no detectable effect on gross or microscopic appearance of the liver, spleen, kidneys, heart, lungs or brain. Blood counts and chemistries remained within normal limits. We conclude that single doses of ZnMP-serum albumin are nontoxic, rapidly cleared from the plasma and persist primarily in the liver and spleen where heme oxygenase is inhibited for prolonged periods.
Asunto(s)
Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Metaloporfirinas/farmacocinética , Animales , Masculino , Metaloporfirinas/administración & dosificación , Metaloporfirinas/farmacología , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
We characterize a liver cell culture model for acute hepatic porphyrias that recapitulates the biochemical features of the human syndrome. In chick embryo liver cells in primary culture exposed to glutethimide and 4,6-dioxoheptanoic acid, heme alone produced a transient dose-dependent decrease in delta-aminolevulinate synthase and a concomitant increase in heme oxygenase. The addition of low concentrations of zinc-mesoporphyrin (50-200 nM), an inhibitor of heme oxygenase, led to more prolonged decreases in activity of the synthase and to an additive effect with heme. These effects of zinc-mesoporphyrin were associated with prolonged inhibition of heme oxygenase. These results suggest that the treatment of choice of acute porphyric syndromes may be the combination of low doses of heme and zinc-mesoporphyrin or another similarly non-toxic inhibitor of heme oxygenase.
Asunto(s)
5-Aminolevulinato Sintetasa/metabolismo , Hemo/farmacología , Hígado/enzimología , Metaloporfirinas/farmacología , Porfirias/enzimología , 5-Aminolevulinato Sintetasa/biosíntesis , Animales , Células Cultivadas , Embrión de Pollo , Relación Dosis-Respuesta a Droga , Represión Enzimática , Compuestos Férricos/farmacología , Glutetimida/farmacología , Hemo Oxigenasa (Desciclizante)/metabolismo , Heptanoatos/farmacología , Cinética , Hígado/efectos de los fármacos , Ácido Nitrilotriacético/análogos & derivados , Ácido Nitrilotriacético/farmacologíaRESUMEN
Administration of reserpine, an inhibitor of vesicular catecholamine storage, differentially reduced the accumulation of MPP+ formed from MPTP in rats and mice. The effects were most pronounced in the adrenal gland for either species. In rats, reserpine decreased striatal and hippocampal MPP+ levels while in mice reserpine did not affect the disposition of MPP+ in the striatum but decreased hippocampal MPP+. The data suggest that mice may be more sensitive to the toxicant because less striatal MPP+ appears to be stored in the reserpine-sensitive storage vesicle.
Asunto(s)
1-Metil-4-fenilpiridinio/metabolismo , Intoxicación por MPTP , Receptores de Catecolaminas/efectos de los fármacos , Reserpina/farmacología , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Especificidad de la EspecieRESUMEN
Black people have a lower plasma renin activity (PRA) than is appropriate for the level of blood pressure, but the mechanism remains unknown. Studies in our laboratory, using the hypophysectomised (Hypox) rat model, have provided a partial explanation of the inappropriately low PRA with respect to BP. Kidneys were isolated and perfused and renin secretion responsiveness studied with isoproterenol (Iso) infusion, calcium (Ca) depletion, and pressure reduction; an enriched preparation of juxtaglomerular (JG) cells was prepared for determination of cellular renin content (CRC); and preparations of isolated renin granules (IRG) and plasma membrane vesicles (PMV) from the purified JG cells were used to assess the storage and compartmentalisation of renin. Renin secretion was lower in Hypox than in normal and sodium (Na) deprived rats. On the other hand, CRC, IRG, and PMV were identical (statistically) in Hypox and Na deprived rats. Despite identical content and storage, kidneys from Hypox rats secreted significantly less renin in response to Iso, Ca depletion, and low pressure. One interesting observation is that upon stimulation, PMV of Hypox rats stored a much larger percentage of renin than normal or Na deprived rats, suggesting that the PMV may play a role as a renin sink in the low PRA levels observed in the Hypox rats. Since black people have renin profiles and responsiveness similar to those in Hypox rats, this model may be useful in studying the mechanisms responsible for their lower PRA.
Asunto(s)
Población Negra , Hipofisectomía , Renina/sangre , Animales , Humanos , RatasRESUMEN
The distribution of the cells of origin of the cervical vagus and cardiopulmonary nerves has been studied in neonatal piglets (Sus scrofa) ranging in age from 1 to 60 days. Cardiopulmonary nerves were identified physiologically and anatomically prior to injection of horseradish peroxidase (HRP) into the nerves. Following injection of HRP into the cervical vagus nerve retrogradely labeled neurons were present in the dorsal motor nucleus of the vagus nerve (DMV), the nucleus of the solitary tract, the nucleus ambiguus (NA), ventrolateral to the NA and in an intermediate zone between the DMV and the NA. Two unique clusters of neurons were also retrogradely labeled after injections into the vagus nerve. One group was located lateral to the most caudal levels of the DMV and extended as far caudally as the C1 spinal segment. The second distinctive group was located ventrolateral to the nucleus ambiguus in a cell column identified as the ventrolateral nucleus ambiguus (VLNA). After injections of HRP into cardiopulmonary nerves, the majority of neurons were found in the VLNA and the distinct clusters of neurons in this cell column were particularly heavily labeled. Small numbers of cells were labeled in the DMV and NA and none were labeled in the solitary nucleus after cardiopulmonary nerve injections. There were no apparent age-related differences in the degree or distribution of retrograde labeling. The distribution of neurons in the medulla oblongata projecting into cardiopulmonary nerves in the piglet is similar to that described in other species, i.e., the nucleus ambiguus, particularly its ventrolateral cell column, is the primary site of cardiomotor neurons. In addition, in the piglet there is a morphologically distinct cluster of cells related to the heart, and possibly the lungs, which does not appear to be present in other species.