INHIBITION OF GROWTH OF MYELOMA CELLS

抑制骨髓瘤细胞的生长

• 批准号: 3460364
• 负责人: CARL E FRETER
• 金额: $ 10.16万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 1997-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3460364
• 关键词: 3T3 cells; B lymphocyte; SDS polyacrylamide gel electrophoresis; antibody formation; antibody receptor; athymic mouse; bioassay; cell growth regulation; cell line; complementary DNA; disease /disorder model; enzyme linked immunosorbent assay; glucocorticoids; growth inhibitors; high performance liquid chromatography; immunoconjugates; interleukin 6; laboratory mouse; messenger RNA; multiple myeloma; myeloma globulin; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; northern blottings; nucleic acid probes; paracrine; polymerase chain reaction; protein biosynthesis; suramin

Multiple myeloma is a malignancy of the plasma cell, the final stage of differentiation of the B-lymphocyte. The average age-adjusted incidence of multiple myeloma in the US is 3.0/100,000. Multiple myeloma is the second most common lymphoid malignancy in whites, and the most common lymphoid malignancy in blacks. A major contributor to the morbidity and mortality of multiple myeloma is the unregulated production of immunoglobulin resulting in renal failure, hyperviscosity, and amyloid deposition with end-organ damage. Hence, treatment strategies directed not only at growth inhibition of the malignant cell, but also inhibition of immunoglobulin secretion may alter both morbidity and mortality of multiple myeloma. The multifunctional cytokine IL-6 has been proposed as an autocrine or paracrine mediator of myeloma cell growth and immunoglobulin secretion. Previous work in our laboratory has shown that in vitro glucocorticoids and the polysulfonated napthylurea suramin synergistically inhibit the growth of human multiple myeloma cell lines. In addition, we have demonstrated that both these agents inhibit immunoglobulin secretion in human multiple myeloma cell lines at minimally growth inhibitory (IC10) concentrations. This proposal is aimed at directly experimentally testing the following specific hypotheses: 1. The lymphokine IL-6 is an autocrine or paracrine growth factor for both growth and immunoglobulin production in multiple myeloma. 2. Glucocorticoids and/or suramin exert inhibitory effects on myeloma growth and immunoglobulin secretion by interfering with the action of IL-6. Objectives: 1. A panel of human, B-cell, immunoglobulin-secreting, glucocorticoid sensitive multiple myeloma cell lines will be selected and characterized for both in vitro and in vivo studies. 2. The expression of IL-6 protein, mRNA and receptor sites will be determined in this panel of cell lines in response to treatment with glucocorticoids and suramin to test the hypothesis that these agents block IL-6 dependent growth and immunoglobulin secretion. 3. The mechanism by which suramin and glucocorticoids inhibit the elaboration of immunoglobulin from human myeloma cells will be examined. 4. The ability of an available IL-6-binding polyclonal antibody to block immunoglobulin secretion will be determined to test the hypothesis that IL- 6 functions as an autocrine or paracrine stimulator of immunoglobulin secretion in multiple myeloma. 5. An animal model (NIH-3 mouse) will be established for in-vivo study of inhibition of growth and immunoglobulin secretion and the growth regulatory role of IL-6 in heterografted human multiple myeloma cells.

多发性骨髓瘤是浆细胞的恶性肿瘤，是 B淋巴细胞的分化。 平均年龄调整的发生率 美国多发性骨髓瘤为3.0/100,000。 多发性骨髓瘤是第二个 白人中最常见的淋巴性恶性肿瘤和最常见的淋巴样 黑人的恶性肿瘤。 发病率和死亡率的主要贡献者 多发性骨髓瘤是免疫球蛋白的不受管制的产生 与 最终器官损坏。 因此，不仅针对增长的治疗策略 抑制恶性细胞，但也抑制免疫球蛋白 分泌可能会改变多发性骨髓瘤的发病率和死亡率。 多功能细胞因子IL-6已被提议为自分泌或 骨髓瘤细胞生长和免疫球蛋白分泌的旁分泌介质。 我们实验室的先前工作表明，体外糖皮质激素和 多硫化的萘脲苏拉素协同抑制了生长 人类多发性骨髓瘤细胞系的。 此外，我们已经证明了 这两种药物都抑制人类多重的免疫球蛋白分泌 在最小生长抑制（IC10）浓度下的骨髓瘤细胞系。 该建议旨在直接实验测试以下 特定的假设： 1。淋巴细胞因子IL-6是两者的自分泌或旁分泌生长因子 多发性骨髓瘤的生长和免疫球蛋白产生。 2。糖皮质激素和/或苏拉明对骨髓瘤产生抑制作用 通过干扰IL-6的作用，生长和免疫球蛋白分泌。 目标： 1。人，B细胞，免疫球蛋白分泌，糖皮质激素 将选择并表征敏感的多发性骨髓瘤细胞系 用于体外和体内研究。 2。IL-6蛋白，mRNA和受体位点的表达将是 在此细胞系中确定的，以响应于 糖皮质激素和苏拉蛋白测试这些药物阻止的假设 IL-6依赖性生长和免疫球蛋白分泌。 3。苏拉明和糖皮质激素抑制的机制 将检查从人骨髓瘤细胞中阐述免疫球蛋白。 4。可用的IL-6结合多克隆抗体阻断的能力 免疫球蛋白分泌将确定以检验以下假设。 6起免疫球蛋白的自分泌或旁分泌刺激剂 多发性骨髓瘤的分泌。 5。将建立动物模型（NIH-3小鼠）以进行体内研究 抑制生长和免疫球蛋白分泌和生长调节 IL-6在异质移植的人类多发性骨髓瘤细胞中的作用。