Lymphoma and Its Response to Treatment

淋巴瘤及其对治疗的反应

• 批准号: 6984597
• 负责人: Janet F. Eary
• 金额: $ 9.35万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-10 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6984597
• 关键词: DNA replication; antineoplastics; antitumor antibody; bioimaging /biomedical imaging; biomarker; cell death; cell proliferation; clinical research; combination cancer therapy; flow cytometry; human subject; human therapy evaluation; image guided surgery /therapy; laboratory mouse; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplastic growth; nonHodgkin' s lymphoma; patient oriented research; positron emission tomography; prognosis; radionuclides

Non-Hodgkin's lymphoma is a tumor consisting of malignant B-cell lymphocytes that presents with a spectrum of tumor grades and stages. Treatment strategies result in high response rates, however, eventually two-thirds of all tumors become treatment resistant and are fatal. Developments in molecular biology have shown that lymphoma malignant behavior is directly related to the balance between increased cellular proliferation and decreased cell death. Recently, widespread use of anti-CD-20 antibody for indolent lymphomas has demonstrated high levels of response, without the toxicity observed with chemotherapeutic agents. The mechanisms through which anti-CD-20 antibodies exert their treatment effects are controversial, but probably relate to a variety of immunological mechanisms that result in induction of tumor cell death. Treatment for more aggressive tumors often involves a combination of anti-CD-20 antibody with the conventional combination chemotherapy regimen (CHOP), which is thought to exert a synergistic effect. We will investigate the contribution that biologically specific PET imaging agents can make to evaluation of lymphoma biological activity across the entire spectrum of disease. Imaging will also be used to quantitate specific biological aspects of response to therapy. [C-11]-Thymidine PET will be used to provide quantitative data on tumor DNA synthesis. We will evaluate a new PET imaging agent for quantitating tumor cell death; [F-18]-annexin V binds to membranes that have exposed phosphatidyl serine residues resulting from programmed cell death. [C-11]-thymidine PET imaging will be used to quantitate proliferation as a sensitive agent for identifying lymphoma sites and as a growth rate baseline for quantitating response to treatment. We will use [F-18]-annexin V to quantitate tumor levels of cell death prior to, during and after treatment and we will compare the growth and death images. Image-derived tumor uptake data using these biologically specific agents will be correlated with clinical parameters used in lymphoma clinical diagnosis including histologic type, immunophenotype, Bcl-2 expression, serum LDH and beta2 microglobulin. We will use flow cytometry to quantitate the population of tumor cells in S-phase and haploid type (undergoing programmed cell death). This new imaging information will provide critical insight into treatment effectiveness through different cytotoxic mechanisms for lymphoma treatment and to design of more effective treatment strategies.

非霍奇金淋巴瘤是一种由恶性 B 细胞淋巴细胞组成的肿瘤，具有一系列肿瘤分级和阶段。治疗策略可以带来高反应率，然而，最终三分之二的肿瘤会对治疗产生耐药性并致命。分子生物学的发展表明，淋巴瘤的恶性行为与细胞增殖增加和细胞死亡减少之间的平衡直接相关。最近，抗CD-20抗体广泛用于治疗惰性淋巴瘤，显示出高水平的反应，并且没有化疗药物观察到的毒性。抗CD-20抗体发挥治疗作用的机制存在争议，但可能与多种导致肿瘤诱导的免疫机制有关 细胞死亡。对于更具侵袭性的肿瘤的治疗通常涉及抗 CD-20 抗体与传统联合化疗方案 (CHOP) 的组合，这被认为可以发挥协同作用。我们将研究生物特异性 PET 显像剂对评估整个疾病谱中淋巴瘤生物活性的贡献。成像还将用于定量治疗反应的特定生物学方面。 [C-11]-胸苷 PET 将用于提供肿瘤 DNA 合成的定量数据。我们将评估一种用于定量肿瘤细胞死亡的新型 PET 成像剂； [F-18]-膜联蛋白 V 与因程序性细胞死亡而暴露出磷脂酰丝氨酸残基的膜结合。 [C-11]-胸苷 PET 成像将用于定量增殖，作为识别淋巴瘤部位的敏感剂，并作为定量治疗反应的生长速率基线。我们将使用 [F-18]-annexin V 来定量治疗前、治疗期间和治疗后的肿瘤细胞死亡水平，并比较生长和死亡图像。图像来源的肿瘤 使用这些生物特异性试剂的摄取数据将与淋巴瘤临床诊断中使用的临床参数相关，包括组织学类型、免疫表型、Bcl-2表达、血清LDH和β2微球蛋白。我们将使用流式细胞术来定量 S 期和单倍体型（经历程序性细胞死亡）肿瘤细胞的数量。这些新的成像信息将通过淋巴瘤治疗的不同细胞毒性机制提供对治疗效果的重要见解，并设计更有效的治疗策略。