CANCER THERAPY WITH BIOTHERAPEUTICS CONTAINING GENISTEIN

描述：(申请人的描述)计划的长期目标 研究开发新的高效生物疗法 治疗白血病、淋巴瘤和乳腺癌。异黄酮类染料木素 从假单胞菌发酵液中提取。是一种自然发生的 大豆中存在的酪氨酸激酶抑制剂。有针对性地交付 染料木素通过区域特异性连接到载体分子，已被证明是一种 诱导人类癌症使徒细胞死亡的非常有效的策略 Cells(Uockun等人，Science 267：886-891,1995；Proc.娜塔莉。阿卡德科学公司。 美国92：9575-9579,1995)。CD19受体在体外高水平表达 白血病/淋巴瘤细胞及其与Src原癌基因的物理关联 家族酪氨酸激酶形成膜相关抗细胞凋亡 复合体。表皮生长因子受体(EGF-R)高表达 乳腺癌和前列腺癌细胞的水平，它们也是 与Src家族酪氨酸激酶相关形成至关重要的 膜相关的抗细胞凋亡复合体。我们的初步研究 有力地支持了我们的假设，CD19和EGF受体适合 表膜导向的细胞凋亡诱导策略的靶点 将染料木素输送到CD19或EGF-R相关的重要酪氨酸激酶。 我们临床项目的目标是开发和实施 B43-金雀异黄素作为药物导向的临床肌注方案 抗白血病药物和作为抗乳腺癌药物的EGF-金雀异黄素。它 预计(A)几种新型染料木素偶联物将成为 在预计的赠款期间可用于临床研究和(B) 成功完成拟议的研究将是一个良好的开端 金雀异黄素结合物的应用研究进展 白血病/淋巴瘤和乳腺癌患者。

DESCRIPTION: (Applicant's Description) The long-term goal of the proposed research is the development of novel and highly effective biotherapeutics against leukemias, lymphomas, and breast cancer. Genistein, an isoflavone from fermentation broth of Pseudomonas spp. is a naturally occurring tyrosine kinase inhibitor present in soybeans. The targeted delivery of genistein by regiospecific linkage to carrier molecules has proven to be a very effective strategy for inducing apostolic cell death in human cancer cells (Uckun et al., Science 267: 886-891, 1995; Proc. Natl. Acad Sci. USA 92: 9575-9579, 1995). CD19 receptor is expressed at high levels on leukemia/lymphoma cells and it physically associates with Src protooncogene family tyrosine kinases to form membrane-associated anti-apoptotic complexes. Epidermal growth factor receptors (EGF-R) are expressed at high levels on breast cancer as well as prostate cancer cells and they are also associated with Src family tyrosine kinases to form vital membrane-associated anti-apoptotic complexes. Our preliminary studies strongly support our hypothesis that CD 19 and EGF receptors are suitable targets for a surface membrane directed apoptosis-induction strategy by delivering Genistein to CD19- or EGF-R-associated vital tyrosine kinases. The goal of our Clinical Program is to develop and implement pharmacologically guided clinical Phase IM protocols using B43-genistein as an anti-leukemia agent and EGF-genistein as an anti-breast cancer agent. It is anticipated that (a) several novel genistein conjugates will become available for clinical studies during the projected grant period and (b) successful completion of the proposed studies will constitute a good start towards the application of genistein conjugates for more effective treatment of leukemia/lymphoma and breast cancer patients.