ANTIHORMONAL TO LEUKEMIA--MODIFIED CYTOKINE RECEPTOR

白血病抗激素--修饰细胞因子受体

• 批准号: 2102359
• 负责人: W D HANKINS
• 金额: $ 34.86万
• 依托单位: PROED, INC.
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-04 至 1997-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2102359
• 关键词: antileukemic agent; complementary DNA; cytokine receptors; cytotoxicity; disease /disorder model; drug design /synthesis /production; drug screening /evaluation; erythroleukemia; erythropoiesis; erythropoietin; growth factor receptors; hormone inhibitor; hormone related neoplasm /cancer; polymerase chain reaction; protein purification; protein structure; receptor binding; receptor expression; recombinant DNA; tissue /cell culture

Several years of leukemia research has led the principal investigator to a hypothesis that many cancers remain hormone-dependent, retain the ability to terminally differentiate, and exhibit many normal cell properties. The present study was initiated to exploit one of these properties, namely hormone sensitivity of leukemia cells, in an effort to develop a lineage specific, gentle, safe and effective drug which will destroy leukemia cells. In particular, a drug will be devised which will specifically bind erythropoietin, and in so doing will competitively inhibit growth of erythroleukemia cells which require this hormone for their survival and proliferation. The drug will be composed of the soluble exoplasmic domain of the Epo receptor (solEpoR) which will be expressed and purified through recombinant DNA technology. In phase l, we have shown the feasibility of this project. In particular, we have initiated the synthesis of the human solEpoR, expressed EpoR in bacterial, baculovirus and mammalian systems, demonstrated that solEpoR binds Epo, and most importantly we have determined that solEpoR has the ability to kill Epo- dependent cells. In Phase Il we will scale up production of solEpoR and attempt to prove the efficacy of soluble Epo receptors in inhibiting growth of Epo-dependent leukemias in animal models. In addition we will compare the ability of various mutated EpoRs to inhibit growth of Epo dependent cells to determine which is the best candidate to use as an anti-hormone drug. We believe that this soluble receptor approach to cancer treatment can be generalized to any hormone dependent malignancy. Therefore, we also wish to test this approach using other cytokine receptors which are required for the proliferation of myeloid and lymphoid tumors and perhaps other cancers. PROPOSED COMMERCIAL APPLICATION: Product: A modified cytokine receptor which has been proven to have selective toxicity to cells of a certain hemopoietic lineage. This new form of drug should prove useful in fighting specific cancers or altering specific pathways of differentiation in the body which may be producing hyperplasia.

几年的白血病研究使首席研究员 假设许多癌症仍然依赖于癌症，保留了 具有终末分化能力，并表现出许多正常细胞 特性.本研究旨在利用其中一种 白血病细胞的激素敏感性， 开发一种谱系特异性、温和、安全和有效的药物， 摧毁白血病细胞特别是，将设计一种药物， 特异性结合促红细胞生成素，这样做将竞争性地 抑制红白血病细胞的生长，红白血病细胞需要这种激素 它们的生存和扩散。药物将由可溶性 将被表达的Epo受体的外质结构域（solEpoR） 并通过重组DNA技术纯化。在阶段l中，我们已经表明 这个项目的可行性。特别是， 人solEpoR的合成，在细菌、杆状病毒中表达EpoR 和哺乳动物系统，证明solEpoR结合Epo， 重要的是，我们已经确定solEpoR有能力杀死Epo- 依赖细胞在第二阶段，我们将扩大solEpoR的生产， 试图证明可溶性Epo受体在抑制 Epo依赖性白血病动物模型的生长。此外，我们将 比较各种突变的EpoR抑制Epo生长的能力 依赖细胞，以确定哪一个是最好的候选人， 抗激素药我们相信这种可溶性受体途径 癌症治疗可以推广到任何激素依赖性恶性肿瘤。 因此，我们也希望使用其他细胞因子来测试这种方法 骨髓和淋巴细胞增殖所需的受体 肿瘤和其他癌症。 拟定商业应用：产品：一种修饰的细胞因子受体 它已经被证明对某些特定的细胞具有选择性毒性， 造血谱系这种新药在战斗中应该会很有用 特定的癌症或改变特定的分化途径， 可能产生增生的身体。