ABSTRACT
The iron chelator deferasirox is widely used in patients with iron overload. Patients with low-grade myelodysplastic syndromes (MDS) get transfusion dependency and need to be treated with deferasirox to avoid iron overload. Moreover, in some patients an increase in both erythroid and platelets have been observed after deferasirox therapy. However, the mechanisms involved in these clinical findings are poorly understood. The aim of this work was to analyze, in patients treated with deferasirox, the changes in the gene-expression profile after receiving the treatment. A total of 15 patients with the diagnosis of low-grade MDS were studied. Microarrays were carried out in RNA from peripheral blood before and after 14 weeks of deferasirox therapy. Changes in 1457 genes and 54 miRNAs were observed: deferasirox induced the downregulation of genes related to the Nf kB pathway leading of an overall inactivation of this pathway. In addition, the iron chelator also downregulated gamma interferon. Altogether these changes could be related to the improvement of erythroid response observed in these patients after therapy. Moreover, the inhibition of NFE2L2/NRF2, which was predicted in silico, could be playing a critical role in the reduction of reactive oxygen species (ROS). Of note, miR-125b, overexpressed after deferasirox treatment, could be involved in the reduced inflammation and increased hematopoiesis observed in the patients after treatment. In summary this study shows, for the first time, the mechanisms that could be governing deferasirox impact in vivo.
Subject(s)
Deferasirox/therapeutic use , Erythropoiesis/drug effects , Gene Expression Profiling , Iron Chelating Agents/therapeutic use , Myelodysplastic Syndromes/drug therapy , Transcriptome/drug effects , Aged , Aged, 80 and over , Deferasirox/adverse effects , Erythropoiesis/genetics , Female , Gene Expression Regulation/drug effects , Gene Regulatory Networks/drug effects , Genome-Wide Association Study , Humans , Iron Chelating Agents/adverse effects , Male , Middle Aged , Myelodysplastic Syndromes/blood , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/genetics , Oligonucleotide Array Sequence Analysis , Pharmacogenetics , Treatment OutcomeABSTRACT
Painful bone metastases are common in prostate cancer, with current treatments including non-steroidal analgesics and opiates, surgery, external beam radiotherapy and bone-targeting ß-emitting radiopharmaceuticals. The α-emitting isotope 223Ra-dichloride (Ra-223) has been associated with improved overall survival and increased time to first skeletal-related events in patients with castration-resistant prostate cancer (CRPC) presenting with symptomatic bone metastases. The current study reports the case of a 70-year-old male patient, who was diagnosed with prostate cancer in 1999 upon presentation with increased prostate-specific antigen (PSA) levels and painful bone metastases in the context of CRPC. In November 2010, subsequent to undergoing hormonal blockage, the patient was treated with ketoconazole (200 mg/8 h) followed by 10 cycles of docetaxel (75 mg/m2 every 3 weeks). Following disease progression, the patient received 6 doses of Ra-223 (50 kBq/kg; 1 dose/4 weeks). During this treatment period, an improvement in the patient's symptoms, and levels of bone alkaline phosphatase (BAP) and PSA were noted. Furthermore, Ra-223 was well-tolerated without any relevant bone marrow toxicity. However, 2 months after the administration of the final dose of Ra-223, PSA and BAP levels increased again, and bone pain deteriorated. A bone scan showed stable disease in the previously observed metastatic lesions; however, new lesions simultaneously appeared in different locations, indicating progressive disease.
