IN SITU MEASUREMENT OF CHEMOTHERAPEUTIC DRUG KINETICS IN SOLID TUMORS

实体瘤中化疗药物动力学的原位测量

• 批准号: 6308535
• 负责人: JAMES R BADING
• 金额: $ 2.35万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6308535
• 关键词: Mammalia; bioengineering /biomedical engineering; bioimaging /biomedical imaging; biomedical resource; human tissue; model design /development; positron emission tomography; technology /technique

The long range objective is to develop a method for measuring tumor uptake and metabolic incorporation of 5-fluorouracil (5-FU) in human tumors by positron emission tomography (PET). Fluorouracil is readily labeled with the positron-emitting radionuclide 18F, and PET studies with [18F]5-FU in human cancer patients have been reported. However, interpretation of scan results is obscured by the presence of labeled, recirculating catabolites of [18F]5-FU. Several years ago, researchers at Roswell Park Cancer Institute (Buffalo, NY) and Burroughs-Wellcome Co. (subsequently changed to Glaxo-Wellcome) began reporting marked increases in the effectiveness of 5-FU against mouse and rat tumors when the drug is given in combination with 5-ethynyluracil (5-EU), an inhibitor of dihydropyrimidine dehydrogenase (DPD), the enzyme which catalyzes the first step in the catabolic breakdown of 5-FU within the body. Phase I clinical trials of 5-FU+5-EU have yielded positive results. With catabolism suppressed by 5-EU, PET imaging of [18F]5-FU could be used to accurately quantify tumor incorporation of 5-FU into cytotoxic molecular species, which are retained intracellularly for several hours or more. This study seeks to develop and validate the necessary kinetic imaging and mathematical modeling techniques in a rat, colorectal tumor model. Technical support for the modeling effort is provided by the Center for Bioengineering, University of Washington. Even though it is one of the most widely used chemotherapeutic drugs, the clinical efficacy of 5-FU is highly limited. Combination with 5-EU may render 5-FU far more effective. The ability to measure tumor incorporation of 5-FU noninvasively would also be a major advance, since it would permit individualized treatment planning and identification of those patients unlikely to respond because of inadequate tumor incorporation of 5-FU. Positive results in the experimental rat study are expected to lead to a clinical trial of PET/[18F]5-FU at USC. However, the rat study will itself add significant information about the pharmacokinetics of 5-FU + 5-EU and the usefulness of PET for pharmacokinetic studies, regardless of subsequent studies in humans. Dr. Bading is collaborating with Prof. Walter Wolf, USC B00. of Pharmaceutical Sciences, a leading expert in the in vivo study of 5-FU pharmacokinetics by magnetic resonance spectroscopy (MRS). Together, Drs. Bading and Wolf are developing the combined use of PET and MRS to maximize capability for noninvasive characterization of 5-FU kinetics in experimental models and human patients. The objectives of the project are summarized below. Specific Aims 1 and 2 have been completed; work on Specific Aim 3 is in progress. Specific Aim 1: Demonstrate sensitivity of rat tumor to 5-FU + 5-EU. When subcutaneously implanted tumors have grown to 5 g, the rats will be treated with i.v. 5-FU alone or i.v. 5-FU + i.p. 5-EU using doses and schedule specified by Burroughs Wellcome. Tumor size will be measured periodically during a 2 wk follow-up period to determine response to therapy. Specific Aim 2: Develop techniques for tracer kinetic studies in rats. (physiologic control, vascular access, alignment in PET scanner, validation of quantitative imaging, labeled metabolite identification by HPLC). Specific Aim 3: Use PET, [18F] 5-FU and mathematical modeling to measure 5-FU trapped/g tumor. when 5-FU is given with or without 5-EU). Rats will be pretreated or not with 5-EU (1 mg/kg i.p.). Dynamic imaging and serial arterial blood sampling will be performed for 2 h following bolus i.v. injection of [18F]5-FU. Radio- and HPLC assays will be done on the blood samples as well as tumor tissue excised at the end of the imaging procedure. The resulting data will be used to develop and validate a kinetic model which correctly predicts the amount of 5-FU incorporated into cytotoxic forms within tumor.

长期目标是开发一种测量方法 5-氟尿嘧啶 (5-FU) 的肿瘤摄取和代谢掺入 通过正电子发射断层扫描 (PET) 检测人类肿瘤。 氟尿嘧啶是 易于用正电子发射放射性核素 18F 和 PET 标记 已经报道了在人类癌症患者中使用 [18F]5-FU 进行的研究。 然而，扫描结果的解释因存在 [18F]5-FU 标记的再循环分解代谢物。 几年前， 罗斯威尔帕克癌症研究所（纽约州布法罗）的研究人员和 Burroughs-Wellcome Co.（后来更名为 Glaxo-Wellcome）成立 报告 5-FU 对小鼠的有效性显着增加 当该药物与以下药物联合使用时，和大鼠肿瘤 5-乙炔尿嘧啶 (5-EU)，二氢嘧啶抑制剂 脱氢酶（DPD），催化第一步的酶 体内 5-FU 的分解代谢。 I期临床试验 5-FU+5-EU 已取得积极成果。 具有分解代谢作用 由于 5-EU 的抑制，[18F]5-FU 的 PET 成像可用于 准确量化肿瘤将 5-FU 掺入细胞毒性物质 分子种类，在细胞内保留数年 小时或更长时间。 本研究旨在开发和验证必要的 大鼠的动力学成像和数学建模技术， 结直肠肿瘤模型。 建模工作的技术支持是 由华盛顿大学生物工程中心提供。 尽管它是最广泛使用的化疗药物之一， 5-FU的临床疗效非常有限。 与 组合 5-EU 可能使 5-FU 更加有效。 测量肿瘤的能力 无创地掺入 5-FU 也将是一个重大进步， 因为它将允许个性化的治疗计划和 确定那些不太可能做出反应的患者，因为 5-FU 肿瘤掺入不足。 积极成果 实验性大鼠研究预计将导致临床试验 PET/[18F]5-FU，南加州大学。 然而，老鼠研究本身会增加 有关 5-FU + 5-EU 药代动力学的重要信息和 PET 在药代动力学研究中的有用性，无论 随后的人类研究。 Bading 博士正在与 Prof. 沃尔特·沃尔夫，南加州大学 B00。 制药科学领域的领先专家 磁共振体内5-FU药代动力学研究 光谱（MRS）。 在一起，博士。巴丁和沃尔夫正在开发 结合使用 PET 和 MRS，最大限度地提高无创性 实验模型和人体中 5-FU 动力学的表征 患者。 该项目的目标概述如下。 具体目标1和2已经完成；具体目标 3 的工作是 进行中。 具体目标 1：证明大鼠肿瘤对 5-FU + 5-EU。 当皮下植入的肿瘤长到5克时， 老鼠将接受静脉注射治疗。单独使用 5-FU 或静脉注射5-FU + 腹腔注射5-欧盟 使用 Burroughs Wellcome 规定的剂量和时间表。 肿瘤大小 将在 2 周的随访期间定期进行测量，以 确定对治疗的反应。 具体目标 2：开发技术 用于大鼠示踪动力学研究。 （生理控制、血管 访问、PET 扫描仪对准、定量成像验证、 通过 HPLC 鉴定标记代谢物）。 具体目标 3：使用 PET， [18F] 5-FU 和数学模型来测量捕获的 5-FU/g 肿瘤。 当 5-FU 与或不与 5-EU 一起给予时）。 将对大鼠进行预处理或 不适用于 5-EU（1 mg/kg i.p.）。动态成像和串行动脉 静脉推注后 2 小时将进行血液采样。 注射[18F]5-FU。 放射性和 HPLC 测定将在 血液样本以及在实验结束时切除的肿瘤组织 成像过程。 由此产生的数据将用于开发和 验证正确预测 5-FU 量的动力学模型 并入肿瘤内的细胞毒性形式。