RESUMEN
Previous studies have suggested that oral zinc supplementation can help reduce the duration of the common cold; however, the use of intranasal (IN) zinc is strongly associated with anosmia, or the loss of the sense of smell, in humans. Prior studies from this lab showed that upregulation of metallothioneins (MT) is a rapid and robust response to zinc gluconate (ZG). Therefore, we assessed the role of MT in the recovery of nasal epithelial damage resulting from IN zinc administration. The main studies in this investigation used a high dose of ZG (170mM) to ensure ablation of the olfactory mucosa, so that the progression of histological and functional recovery could be assessed. In vivo studies using wild-type, MT1/2 knockout mice (MT KO), and heterozygotes administered ZG by IN instillation showed profound loss of the olfactory mucosa in the nasal cavity. Recovery was monitored, and a lower percentage of the MT KO mice were able to smell 28 d after treatment; however, no significant difference was observed in the rate of cell proliferation in the basal layer of the olfactory epithelium between MT KO and wild-type mice. A lower concentration of ZG (33mM), equivalent to that found in homeopathic IN ZG preparations, also caused olfactory epithelial toxicity in mice. These studies suggest that the use of zinc in drug formulations intended for IN administration in humans must be carefully evaluated for their potential to cause olfactory functional deficits.
Asunto(s)
Gluconatos/toxicidad , Metaloproteinasa 14 de la Matriz/deficiencia , Metaloproteinasa 15 de la Matriz/deficiencia , Trastornos del Olfato/inducido químicamente , Trastornos del Olfato/genética , Mucosa Olfatoria/efectos de los fármacos , Administración Intranasal , Animales , Relación Dosis-Respuesta a Droga , Gluconatos/administración & dosificación , Metaloproteinasa 14 de la Matriz/genética , Metaloproteinasa 15 de la Matriz/genética , Ratones , Ratones Transgénicos , Mucosa Olfatoria/patología , Antígeno Nuclear de Célula en Proliferación/metabolismo , TiazolesRESUMEN
Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 (FLT3) gene occurs in 30% of acute myeloid leukemias (AMLs) and confers a poor prognosis. Thirteen relapsed or chemo-refractory FLT3-ITD(+) AML patients were treated with sorafenib (200-400 mg twice daily). Twelve patients showed clearance or near clearance of bone marrow myeloblasts after 27 (range 21-84) days with evidence of differentiation of leukemia cells. The sorafenib response was lost in most patients after 72 (range 54-287) days but the FLT3 and downstream effectors remained suppressed. Gene expression profiling showed that leukemia cells that have become sorafenib resistant expressed several genes including ALDH1A1, JAK3, and MMP15, whose functions were unknown in AML. Nonobese diabetic/severe combined immunodeficiency mice transplanted with leukemia cells from patients before and during sorafenib resistance recapitulated the clinical results. Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations, and might provide important leads to further improvement of treatment outcome with FLT3 inhibitors.