IN SITU MEASUREMENT OF CHEMOTHERAPEUTIC DRUG KINETICS IN SOLID TUMORS

远程目标是开发一种测量方法 肿瘤对5-氟尿嘧啶(5-Fu)的摄取和代谢参入 人体肿瘤正电子发射断层扫描(PET)。氟尿嘧啶是 容易用发射正电子的放射性核素18F和PET标记 有关[18F]5-FU在人类癌症患者中的研究已有报道。 然而，扫描结果的解释由于存在 标记的、循环的[18F]5-FU分解代谢产物。几年前， 罗斯威尔公园癌症研究所(纽约州布法罗)和 Burroughs-Wellcome Co.(后来更名为葛兰素史克)开始 报道称5-FU对小鼠的药效显著增加 和大鼠肿瘤时，药物联合给药 二氢嘧啶抑制剂5-乙炔基尿嘧啶(5-Eu) 脱氢酶(DPD)，催化第一步的酶 5-FU在体内的分解代谢。I期临床试验 5-FU+5-Eu的治疗取得了积极的效果。有分解代谢 被5-Eu抑制，[18F]5-FU的PET显像可用于 准确定量肿瘤5-FU对细胞毒作用的掺入 分子物种，它们在细胞内保留了几个 几个小时或更长时间。这项研究试图开发和验证必要的 大鼠的运动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。与的组合 5-EU可能使5-FU更加有效。测量肿瘤的能力 非侵入性地掺入5-FU也将是一个重大进展， 因为它将允许个性化的治疗计划和 确定那些不太可能有反应的患者，因为 肿瘤对5-FU的掺入不足。积极的结果在 实验大鼠研究有望导致临床试验 PET/[18F]5-FU在南加州大学。然而，对老鼠的研究本身将增加 关于5-FU+5-Eu药代动力学的重要信息 PET在药代动力学研究中的有用性，无论 随后在人类身上进行的研究。贝丁博士正在与巴丁教授合作。 沃尔特·沃尔夫，南加州大学B00。制药科学部，一位领先的 5-氟尿嘧啶体内药代动力学的磁共振研究 波谱(MRS)。巴丁博士和沃尔夫博士共同开发了 联合使用PET和MRS以最大限度地提高无创能力 5-FU在动物模型和人体内的药代动力学特征 病人。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 正在进行中。具体目标1：展示大鼠肿瘤对 5-FU+5-Eu。当皮下移植的肿瘤生长到5g时， 这些大鼠将接受静脉注射治疗。5-FU单独或静脉注射。5-氟尿嘧啶+ip。5-欧盟 使用Burroughs Wellcome指定的剂量和时间表。肿瘤大小 将在2周的随访期内定期测量，以 确定对治疗的反应。具体目标2：开发技术 用于老鼠体内的示踪剂动力学研究。(生理控制、血管 进入，在PET扫描仪中对准，验证定量成像， 用高效液相色谱法鉴定标记代谢物)。具体目标3：使用PET， [18F]5-FU和数学模型测定每克肿瘤的5-FU含量。 当5-FU与5-EU一起或不与5-EU一起给药时)。大鼠将被预先处理或 不含5-Eu(1 mg/kg ip)。动态成像与连续动脉 静脉推注后采血2小时。 注射[18F]5-FU。放射和高效液相色谱分析将在 血液样本以及在手术结束时切除的肿瘤组织 成像程序。所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 在肿瘤内结合成细胞毒性形式。

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.