| Vascular endothelial growth factor(VEGF) plays an important role in angiogenesis acting as a potent inducer of vascular permeability as well as serving as a specific endothelial cell mitogen by interaction of VEGF with its receptor Flt-1 and KDR. In recent investigations the role of angiogenesis in the growth ,dissemination and metastasis of solid tumors has been clearly established. Similar to solid tumor, there is significantly higher microvessel density and over-expression of VEGF in bone marrow of patients with hematopoietic malignancies, and angiogenesis is associated with the development and progression of the disease.To explore the potential role of VEGF in the pathogenesis of patients with leukemia, we first measured VEGF levels in the serum of untreated 49 acute myelogenous leukemia (AML) and 17 chronic myelogenous leukemia (CML) patients using enzyme linked -immunosorbent assay(ELISA). Our data show that 201.17+110.93 pg/ml of VEGF levels in the serum of AML cases was obviously higher than 133.37 + 48.05 pg/ml of control group (PO.05) , whereas 517.79 + 372.49 pg/ml of that in the serum of CML cases was 3.9 times as much as that of the normal control (PO.001), and was one time higher than that of AML. The differences of VEGF concentration in all subtypes of AML were not observed, but APL patients had the highest serum levels of VEGF (299.3 l + 128.45pg/ml). AML and CML patients have an abnormal high expression of VEGF suggesting that vascularity and angiogenic factors may play a important role in the leukemogenic process.Based on the evidence that VEGF plays an important role in leukemia angiogenesis, many researchers are seeking to different angiogenic inhibitors. Arsenic trioxide (As2O3 )has recently been used successfully in the treatment of acute promyelocytic leukemia and has been shown to induce partial differentiation and apoptosis of leukemic cells in vitro.lt was reported recently that As2O3 has potential antiangiogenic activity .In order to further investigate the mechanisms of As2O3, we selected leukemic cell lines K562 U937 NB4 TF-1 as model system and analyzed the expression of VEGF mRNA and protein levels in cultural supernatants isolating from leukemic cell lines using cells culture , reverse transcriptase polymerase chain reaction(RT-PCR) and ELISA. And observed the effects of As2O3 on VEGF expression of leukemic cell lines. VEGF transcripts were detected in all of the four leukemic cell lines. As2O3 for 48 hours (2.5 X 10"6 mol/L and 5X 10"6 mol/L) induced down-regulation of VEGF mRNA was observed. VEGF concentrations of cultural supernatants were high in all of the four leukemic cell lines, expression of VEGF significantly reduction in the presence of (2.5 X 10'6 mol/L and 5 X 10'6 mol/L) As2O3 for 48 hours in U937> K562, TF-1 and NB4 . Treatment of K562 with As2O3 for 48 hours resulted in a 43.2% and 64.3% reduction respectively. These observations suggest that VEGF, an effector of angiogenesis, may play an important role in growth and proliferation of hematopoietic malignancies cells. As2O3 may interrupt angiogenesis by inhibiting VEGF production of leukemic cells.Based on these investigations, we observed the effects of As2O3 on VEGF expression of fresh CML cells (chronic phase ^ accelerate phase blastic crisis). Supernatants of bone marrow cells from 35 CML patients in chronic phase accelerate phase and blastic crisis (649.16 + 382.20pg/mK 560.27 + 409.14 pg/ml fP 587.18 + 415.28 pg/ml) contained significantly more VEGF than that from 15 normal donors (152.16 150.09pg/ml)(P<0.01), but no statistical variation on VEGF concentration was found among the patients with CML of three phases. Whereas VEGF concentrations of CML (chronic phase accelerate phase blastic crisis) fresh cells treatment with(5 X 10~6 mol/L) As2O3 for 72 hours resulted in significant reduction, were 396.66+257.47pg/ml 363.42+239.85pg/ml and 407.47 + 219.38pg/ml respectively (PO.05). These results indicate that As2O3 not only act as inducing apoptosis but also serve...
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