The Study Of The Angiogenesis In The Bone Marrow Of Patients With Myelodysplastic Syndromes And The Mechanism Of Anti-angiogenic Drugs

Angiogenesis is the generation of new capillaries from preexisting blood vessels, is a multistep process. Angiogenesis is co-regulated by angiogenic factors and angiogenesis inhibitors. Moreover, large bodies of studies indicate that angiogenesis of capillaries is associated with the development of neoplastic lesions. And there is increasing evidence that antiangiogenic therapies may induce tumor dormancy or stabilization. Recently, a role for angiogenesis in the pathophysiology of hematologic malignancies has been suggested.Myelodysplastic syndrome (MDS),a clonal hematopoietic stem cell disorder,may progress to acute leukemia in some cases. Some investigators are interested in whether angiogenesis plays a role in the pathophysiology of MDS. Recent studies showed that the microvessels in the bone marrow of patients with MDS were higher than that in normal controls, but whether the microvessels in the bone marrow of patients with MDS is lower than that in acute myeloid leukemia remains poorly understood.Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor(bFGF), the mitogenic activator of vascular endothelial cell,are the most effective, specific and popular angiogenesis regulator studied now. They play an important role in tumor angiogenesis. There are conflict results about whether theexpression of VEGF and bFGF in the bone marrow of patients with MDS is higher than that in normal controls.In 1994, the Folkman group has reported thalidomide inhibits angiogenesis. It was suggested that thalidomide acts as an anti-angiogenesis drug via the generation of toxic hydroxyl radicals,and its process in detail remains unclear. Thalidomide has been recently found to induce a clinical response in about one third of refractory or relapsed myeloma and MDS patients. But it is still unclear whether its clinical effect is mediated, at least in part,by its anti-angiogenesis properties. Whether thalidomide inhibits the proliferation of bone morrow primary cells and the expression of angiogenic genes or by the pathway of inhibiting the proliferation of vascular endothelial cells and its expression of angiogenic associated genes in bone microenvironment hasn't been reported up to date.Three sections were included in this study: (1)The preliminary study of the angiogenesis in the bone marrow of patients with myelodysplastic syndromes. (2)The preliminary study of the angiogenesis factors in the bone marrow of patients with myelodysplastic syndromes. (3) Study on mechanisms of the antiangiogenesis of thalidomide in vitro.To investigate the angiogenesis in the bone marrow of patients with MDS, bone marrow samples from 38 cases of MDS and 30 cases of the control(including 15 cases of acute myeloid leukemia, 15 cases of normal volunteers)were studied. Microvessels were counted by immunohistochemical identification of microvascular endothelial cells with anti-human von Willebrand factor (vWF) throughout the entire core specimen inconsecutive X400 fields, and a mean count per field (/X400 field)was calculated. The microvessels in the bone marrow of patients with MDS was higher than in normal controls (17?/X400field vs 7 ± 2/X400 field, P<0.001) , but lower than in acute myeloid leukemia (24 ± 4/X400 field) . Microvessels counts had no difference between high risk group subtype and lower risk group of MDS (P > 0. 05). There was no correlationbetween microvessels counts and the percentage of blasts in the bone marrow .Angiogenesis may play a role in the pathophysiology of MDS and anti-angiogenesis couldconstitute a novel strategy for the treatment of MDS.To explore the possible effects of VEGF and bFGF on MDS pathophysiology, we usedsemi-quantitative RT-PCR to evaluate the VEGF and bFGF mRNA expression of bone marrowMNCs and ELISA to evaluate the VEGF and bFGF level in bone marrow fluid and in culturesupernatant of MNCs in patients with MDS.We detected the VEGF mRNA expression of bone marrow MNCs in 37 patients with MDSand in 15 normal controls by RT-PCR. The speci...