RESUMEN
Background: Patients with high-risk neuroblastoma (NB) have a 5-year event-free survival of less than 50 %, and novel and improved treatment options are needed. Radiolabeled somatostatin analogs (SSTAs) could be a treatment option. The aims of this work were to compare the biodistribution and the therapeutic effects of 177Lu-octreotate and 177Lu-octreotide in mice bearing the human CLB-BAR NB cell line, and to evaluate their regulatory effects on apoptosis-related genes. Methods: The biodistribution of 177Lu-octreotide in mice bearing CLB-BAR tumors was studied at 1, 24, and 168 h after administration, and the absorbed dose was estimated to tumor and normal tissues. Further, animals were administered different amounts of 177Lu-octreotate or 177Lu-octreotide. Tumor volume was measured over time and compared to a control group given saline. RNA was extracted from tumors, and the expression of 84 selected genes involved in apoptosis was quantified with qPCR. Results: The activity concentration was generally lower in most tissues for 177Lu-octreotide compared to 177Lu-octreotate. Mean absorbed dose per administered activity to tumor after injection of 1.5 MBq and 15 MBq was 0.74 and 0.03 Gy/MBq for 177Lu-octreotide and 2.9 and 0.45 Gy/MBq for 177Lu-octreotate, respectively. 177Lu-octreotide treatment resulted in statistically significant differences compared to controls. Fractionated administration led to a higher survival fraction than after a single administration. The pro-apoptotic genes TNSFS8, TNSFS10, and TRADD were regulated after administration with 177Lu-octreotate. Treatment with 177Lu-octreotide yielded regulation of the pro-apoptotic genes CASP5 and TRADD, and of the anti-apoptotic gene IL10 as well as the apoptosis-related gene TNF. Conclusion: 177Lu-octreotide gave somewhat better anti-tumor effects than 177Lu-octreotate. The similar effect observed in the treated groups with 177Lu-octreotate suggests saturation of the somatostatin receptors. Pronounced anti-tumor effects following fractionated administration merited receptor saturation as an explanation. The gene expression analyses suggest apoptosis activation through the extrinsic pathway for both radiopharmaceuticals.
Asunto(s)
Clorambucilo/efectos adversos , Leucemia Mieloide Aguda/etiología , Linfoma no Hodgkin/terapia , Prednisona/efectos adversos , Autopsia , Médula Ósea/patología , Células de la Médula Ósea , Humanos , Inmunoglobulinas/sangre , Cariotipificación , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Ganglios Linfáticos/patología , Linfoma no Hodgkin/complicaciones , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/enzimología , Linfoma no Hodgkin/inmunología , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Muramidasa/sangre , Neoplasias Primarias Múltiples/patologíaAsunto(s)
Antibacterianos/administración & dosificación , Infecciones Bacterianas/prevención & control , Leucemia/tratamiento farmacológico , Micosis/prevención & control , Enfermedad Aguda , Administración Oral , Adolescente , Adulto , Anciano , Agranulocitosis/complicaciones , Antibacterianos/uso terapéutico , Heces/microbiología , Femenino , Gentamicinas/administración & dosificación , Gentamicinas/uso terapéutico , Humanos , Leucemia/complicaciones , Leucemia/microbiología , Leucemia/mortalidad , Masculino , Persona de Mediana Edad , Neutrófilos , Nistatina/administración & dosificación , Nistatina/uso terapéutico , Remisión Espontánea , Vancomicina/administración & dosificación , Vancomicina/uso terapéuticoRESUMEN
A case of agranulocytosis is reported in which amodiaquine, to which the patient had been exposed, was found to be toxic to the patient's bone marrow cells when these were cultured in an agar colony system in vitro. This technique should be investigated in other patients with agranulocytosis as a possible means of detecting toxic agents.