SYNERGISTIC CHEMO RADIOIMMUNOTHERAPY FOR B LYMPHOMAS

B 淋巴瘤的协同化疗放射免疫治疗

• 批准号: 6613997
• 负责人: TIMOTHY A JOHNSON
• 金额: $ 13.33万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6613997
• 关键词: B cell lymphoma; DNA damage; DNA repair; SCID mouse; antileukocyte isoantibody; apoptosis; athymic mouse; combination cancer therapy; cytosine arabinoside; drug interactions; fludarabine; iodine; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer radioimmunotherapy; nonhuman therapy evaluation; radionuclides

The long-term objectives of this proposal are 1) to improve therapy for non-Hodgkin's lymphoma using combinations of radioimmunotherapy and chemotherapy and 2) to discern the intracellular mechanisms responsible for the synergistic cytotoxicity mediated by these two therapeutic modalities. Preliminary data demonstrate marked synergism in vitro between Iodine-131-radiolabeled anti-CD20 antibody and nucleoside analogs; moderate synergism with topoisomerase inhibitors; and non synergism with cisplatin or 4-hydroxycyclophosphamide. The specific aims of this proposal are four-fold. First, we will test the hypothesis that nucleoside analogs are a more potent class of radiosensitizing drugs for use with I-131-anti-CD20 antibodies than other drug classes using human-derived lymphoma cell lines in vitro. Conclusions will be confirmed in three different in vitro cytotoxic assays, including a clonogenic outgrowth assay, and data will be analyzed by a rigorous isobolographic methodology. Second, we will investigate the mechanisms involved in the potent synergism observed with the nucleoside analogs by assaying well-established effects of the analogs, including the induction of apoptosis, the enhancement of radiation- induced DNA damage, and the incorporation of nucleoside analog into repair DNA. Third, we will investigate the role of Fs-dependent apoptosis in the synergism between anti-CD20 radioimmunotherapy and nucleoside analogs. Fas-dependent and Fas-independent signaling will be studied in experiments employing specific anti-Fas receptor and anti-Fas ligand blocking antibodies, soluble protein inhibitors of the caspase proteins, and immunoblotting of activated forms of caspase 3 (CPP32), caspase 8 (FLICE), and poly-(ADP-ribose) polymerase. Fourth, the most promising combinations of radiolabeled anti-CD20 antibody and chemotherapy will be tested for efficacy in two mouse tumor xenograft models, including a subcutaneous tumor model in nude mice and a disseminated tumor model in SCID mice. The proposed studies will be performed in the laboratory of Dr. Oliver Press at the University of Washington. The large patient base and intense focus on the treatment of lymphomas and other hematologic malignancies at both the University of Washington and the Fred Hutchinson Cancer Research Center and the expertise of the radioimmunotherapy group at these institutions will facilitate rapid translation of promising combinations of radioimmunotherapy and chemotherapy into clinical trials.

该提案的长期目标是1）使用放射免疫疗法和化学疗法的组合改善非霍奇金淋巴瘤的治疗，以及2）辨别负责由这两种治疗方式介导的协同细胞毒性的细胞内机制。初步数据表明，在碘131-二核标记抗CD20抗体和核苷类似物之间的体外协同作用。与拓扑异构酶抑制剂的中等协同作用；和非顺铂或4-羟基环磷酰胺的非协同作用。该提案的具体目的是四倍。首先，我们将检验以下假设：核苷类似物比使用人类衍生的淋巴瘤细胞系中的其他药物类别比其他药物类别更有效，可与I-131-ANTI-CD20抗体一起使用。结论将在三种不同的体外细胞毒性测定中得到证实，包括克隆生成的生长测定，数据将通过严格的同胞方法分析。其次，我们将通过分析类似物的良好效应，包括诱导凋亡，增强辐射诱导的DNA损伤以及将核苷类似物掺入修复DNA中，研究与核苷类似物观察到的有效协同作用的机制。 第三，我们将研究FS依赖性凋亡在抗CD20放射免疫疗法和核苷类似物之间的协同作用中的作用。 Fas-dependent and Fas-independent signaling will be studied in experiments employing specific anti-Fas receptor and anti-Fas ligand blocking antibodies, soluble protein inhibitors of the caspase proteins, and immunoblotting of activated forms of caspase 3 (CPP32), caspase 8 (FLICE), and poly-(ADP-ribose) polymerase.第四，将测试放射标记抗CD20抗体和化学疗法的最有希望的组合，将在两种小鼠肿瘤异种移植模型中测试疗效，包括裸鼠中的皮下肿瘤模型和SCID小鼠中传播的肿瘤模型。拟议的研究将在华盛顿大学奥利弗出版社的实验室进行。在华盛顿大学和弗雷德·哈钦森癌症研究中心的淋巴瘤和其他血液系统恶性肿瘤的治疗以及这些机构的放射免疫疗法组的专业知识以及其他机构的专业知识中，大量的患者基础和强烈的关注将有助于快速转化放射疗法和化学疗法为临床试验。