OBJECTIVE: To investigate the effect of local administration of deferoxamine mesylate (DFO) on vascularization and osteogenesis and its ability to maintain the activity of hypoxia inducible factor-1α (HIF-1α), by constantly observing early changes of vessel-like structures and bone tissues during bone defects healing. METHODS: Skull critical bone defect models were constructed on a total of thirty male SD rats (6-8 weeks old). The rats were randomly divided into experimental group (DFO group) or control group (normal saline group). 300 μL 200 μmol/L DFO solution or normal saline was locally injected on the 4th day after the defect was made. On the 5th, 7th, 10th, 14th, and 28th days after surgery, three rats in each group were sacrificed respectively. HE staining and Masson staining were performed to observe new bone formation and mineralization. HIF-1α immunohistochemistry staining was performed to examine relative expression of protein. Qualitative analysis and comparation were performed by t-tests on relative expression of HIF-1α, numbers of blood vessels and percentages of mineralization tissues of new bone areas. RESULTS: On the 5th, 7th, 10th, 14th and 28th days after surgery, the average numbers of blood vessels were 30.40±12.15, 62.00±17.87, 73.43±15.63, 40.00±7.84, 48.71±11.64 in the DFO group, and 18.75±6.63, 19.13±2.80, 51.35±16.21, 27.18±7.32, 30.88±13.43 in the control group. The number of blood vessels in the DFO group was significantly higher than that of the control group at each time point (P < 0.05). The mass of new bone in the DFO group was higher than that in the control group on the 14th and 28th days after surgery. The percentage of mineralization tissues of new bone area on the 14th and 28th days after injection were (27.73±5.93)% and (46.53±3.66)% in the DFO group, and (11.99±2.02)% and (31.98±4.22)% in the control group. The percentage of mineralization tissues in the DFO group was significantly higher than that of the control group at each time point (P < 0.001). The relative expression of HIF-1α in the DFO group compared with the control group was 2.86±0.48, 1.32±0.26, 1.32±0.32, 1.28±0.38 and 1.05±0.34 on the 5th, 7th, 10th, 14th and 28th days, with significant expression difference on the 5th day (P < 0.01). CONCLUSION Use of DFO in bone defects promotes vascularization and osteogenesis in the defect area, and maintains the protein activity of HIF-1α temporarily.
Animals ; Bone Regeneration ; Deferoxamine/therapeutic use* ; Male ; Rats ; Rats, Sprague-Dawley ; Skull

Adult ; Deferoxamine ; adverse effects ; therapeutic use ; Humans ; Lung Diseases, Interstitial ; chemically induced ; Male ; Myelodysplastic Syndromes ; drug therapy

OBJECTIVETo investigate the effect of deferoxamine (DFO) and DFO in combination with arsenic trioxide (ATO) on inhibition of HL-60 cells xenograft tumor growth in nude mice and its mechanism.

METHODSXenograft tumor model of HL-60 cell line in nude mice was established by inoculating HL-60 cells subcutaneously into nude mice. The tumor-bearing mice were randomly divided into four groups: 50 mg/kg DFO group (group I), 3 mg/kg ATO group (group II), combination group (50 mg/kg DFO + 1.5 mg/kg ATO (group III) and normal saline control group. The drugs were administered intraperitoneally from the day of inoculation (once a day for 10 days). The inhibitory effects on the tumor growth were compared. NF-κBp65 expression levels of the tumors were detected by immunohistochemistry (24h after the last administration).

RESULTS(1) Tumors growth could be observed in all of the nude mice on day 7 to day 8 after inoculation, 0.5 - 1.0 cm in diameter, and then grew rapidly; (2) Tumor weight of control group, group I, group II and group III were (2.62 ± 0.54) g, (2.55 ± 0.82) g, (2.34 ± 0.79) g and (1.95 ± 0.39) g respectively, and the growth inhibition rates in group I, group II and group III were 2.67%, 10.69% and 25.57% respectively. Both DFO alone and in combination with ATO could inhibit the growth of transplanted tumors, and the combination group exhibited more effects, with no vital organ damages in the tumor-bearing mice. (3) There was significant difference in mean value of NF-κBp65 expression among the three experimental groups (P < 0.05), with a descending order of control group > group II, > group I > group III.

CONCLUSION(1) Both DFO and ATO have antitumor activities on tumor-bearing mice, and their combination has an obvious and significant effect. (2) DFO combined with ATO, is well tolerated with no significant adverse effects in the nude mice. (3) Both DFO and ATO can downregulate NF-κBp65 expression of transplanted tumors, especially for their combination.

Animals ; Antineoplastic Agents ; pharmacology ; therapeutic use ; Arsenicals ; pharmacology ; therapeutic use ; Deferoxamine ; pharmacology ; therapeutic use ; Female ; HL-60 Cells ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Oxides ; pharmacology ; therapeutic use ; Transcription Factor RelA ; metabolism ; Xenograft Model Antitumor Assays

A 16-yr-old male patient with hemochromatosis due to multiple packed red blood cell transfusions was referred to our emergency center for the treatment of severe aplastic anemia and dyspnea. He was diagnosed with aplastic anemia at 11-yr of age. He had received continuous transfusions because an HLA-matched marrow donor was unavailable. Following a continuous, approximately 5-yr transfusion, he was noted to develop hemochromatosis. He had a dilated cardiomyopathy and required diuretics and digitalis, multiple endocrine and liver dysfunction, generalized bleeding, and skin pigmentation. A total volume of red blood cell transfusion before deferoxamine therapy was about 96,000 mL. He received a regular iron chelation therapy (continuous intravenous infusion of deferoxamine, 50 mg/kg/day for 5 days q 3-4 weeks) for approximately seven years after the onset of multiple organ failures. His cytopenia and organ dysfunctions began to be gradually recovered since about 2002, following a 4-yr deferoxamine treatment. He showed completely normal ranges of peripheral blood cell counts, heart size, and liver function two years ago. He has not received any transfusions for the last four years. This finding suggests that a continuous deferoxamine infusion may play a role in the immune regulation in addition to iron chelation effect.
Adolescent ; Anemia, Aplastic/pathology/*therapy ; Chelation Therapy/*methods ; Deferoxamine/therapeutic use ; Erythrocyte Transfusion ; Hemochromatosis/*complications/therapy ; Humans ; Immune System ; Iron/*therapeutic use ; Iron Chelating Agents/therapeutic use ; Male ; Radiography, Thoracic/methods ; Time Factors ; Treatment Outcome

OBJECTIVETo investigate whether desferoxamine (DFO) preconditioning can induce tolerance against cerebral ischemia and its effect on the expression of hypoxia inducible factor 1alpha (HIF-1alpha) and erythropoietin (EPO) in vivo and in vitro.

METHODSRat model of cerebral ischemia was established by middle cerebral artery occlusion with or without DFO administration. Infarct size was examined by TTC staining, and the neurological severity score was evaluated according to published method. Cortical neurons were cultured under ischemia stress which was mimicked by oxygen-glucose deprivation (OGD), and the neuron damage was assessed by MTT assay. Immunofluorescent staining was employed to detect the expressions of HIF-1alpha and EPO.

RESULTSThe protective effect induced by DFO (decreasing the infarction volume and ameliorating the neurological function) appeared at 2 d after administration of DFO (post-DFO), lasted until 7 d and disappeared at 14 d (P < 0.05); the most effective action was observed at 3 d post-DFO. DFO induced tolerance of cultured neurons against OGD: neuronal viability was increased 23%, 34%, 40%, 48% and 56% at 8 h, 12 h, 24 h, 36 h, and 48 h, respectively, post-DFO (P < 0.05). Immunofluorescent staining found that HIF-1alpha and EPO were upregulated in the neurons of rat brain at 3 d and 7 d post-DFO; increase of HIF-1alpha and EPO appeared in cultured cortex neurons at 36 h and 48 h post-DFO.

CONCLUSIONDFO induced tolerance against focal cerebral ischemia in rats, and exerted protective effect on OGD cultured cortical neurons. DFO significant induced the expression of HIF-1alpha and EPO both in vivo and in vitro. DFO preconditioning can protect against cerebral ischemia, which may be associated with the synthesis of HIF-1alpha and EPO.

Animals ; Brain Ischemia ; drug therapy ; metabolism ; physiopathology ; Cells, Cultured ; Cerebral Infarction ; drug therapy ; metabolism ; physiopathology ; Deferoxamine ; pharmacology ; therapeutic use ; Disease Models, Animal ; Erythropoietin ; metabolism ; Fluorescent Antibody Technique ; Hypoxia-Inducible Factor 1, alpha Subunit ; drug effects ; metabolism ; Hypoxia-Ischemia, Brain ; drug therapy ; metabolism ; physiopathology ; Infarction, Middle Cerebral Artery ; drug therapy ; metabolism ; physiopathology ; Iron ; metabolism ; Ischemic Preconditioning ; methods ; Nerve Degeneration ; drug therapy ; metabolism ; physiopathology ; Neurons ; drug effects ; metabolism ; pathology ; Rats ; Rats, Sprague-Dawley ; Siderophores ; pharmacology ; therapeutic use ; Time Factors ; Treatment Outcome ; Up-Regulation ; drug effects ; physiology