Bone marrow (BM) angiogenesis is increased in multiple myeloma (MM) and has prognostic value. Anti-angiogenic therapy using thalidomide is being investigated in a clinical trial. The mechanism of this increased angiogenesis and the effect of thalidomide therapy on BM microvessels and angiognenic cytokines are unclear. Preliminary data indicate that normal and malignant plasma cells express the angiogenic cytokines, basic fibroblst growth factor (bFGF) and vascular endothelial growth factor (VEGF). He hypothesizes that plasma cells in myeloma overexpress bFGF and VEGF, and that the increased angiogenesis seen in myeloma is correlated with such overexpression. He also hypothesizes that thalidomide therapy causes regression of BM microvessels and tumor response, and may cause alterations in the expression of VEFG and bFGF. The primary goals of this study are to relate the changes in BM angiogenesis, expression of bFGF, VEGF, and their respective receptors before, during and after thalidomide therapy in 60 patients with myelona treated on a phase II trial. Correlation between the level of angiogenesis and the expression of bFGF, VEGF and their receptors will be studied. Another key aim is to study the implication of changes in BM angiogenesis on the rates of malignant plasma cell apoptosis and proliferation. Differences in angiogenesis and cytokine expression between smoldering/indolent myeloma and relapsed disease will also be studied. BM angiogenesis will be studied using immunohistochemical staining of microvessels for von Willebrand factor and CD34, and estimation of microvessel density and surface area using microscopic and computerized image analysis methods. Immunohistochemistry, in situ hybridization, and serum ELISA assays will be used for the study of bFGF, VEGF, and their receptors. Apoptosis will be measured using sensitive flow cytometric assays that selectively measure tumor cell apoptosis; plasma cells in S-phase and circulating plasma cells will be estimated using slide based bromodeoxyuridine immunofluorescent assays. Paraffin blocks of BM biopsies will be utilized for all immunohistochemical studies, and fresh BM aspirates for apoptosis and proliferation assays. This study offers a unique opportunity to serially study tumor cells and the tumor microenvironment following treatment with an anti-angiogenic agent.
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