PREDICTING TUMOR RESPONSE TO FLUOROURACIL WITH PET

有必要开发准确的方法来预测个体对化疗的反应。放射标记化疗药物的PET成像为解决这一问题提供了一种方法。然而，PET对体内快速分解的药物（如5-氟尿嘧啶（FU））的有用性受到该方法无法直接识别放射性标记的分子关联的限制。我们的长期目标是发展PET作为预测化疗反应和治疗肿瘤疾病个体化方案的工具。我们的中期目标是开发临床实用的PET技术来预测肿瘤对FU的反应。为了发挥作用，FU必须被肿瘤细胞吸收并合成为荧光核苷酸，从而干扰DNA和RNA的合成。德国海德堡的研究人员最近报道，在17例接受转移性结肠癌治疗的患者中，PET测量了肿瘤对FU的反应与[18F]FU放射标记的肿瘤保留呈正相关。虽然很有希望，但这项研究并没有解决循环的，标记的[18F]FU分解代谢物对PET图像的影响，并且所使用的成像技术提供的关于肿瘤中FU动力学的信息很少。我们正在开发一种新的方法，利用生物调节来创建一种能够测量肿瘤运输和FU本身代谢的体内成像技术。具体来说，我们用乙炔尿嘧啶（EU）进行预处理，这是一种有效的FU分解代谢抑制剂，可以防止[18F]FU的降解，从而提高PET对与肿瘤反应最密切相关的FU药代动力学方面的敏感性。我们在大鼠结肠肿瘤模型的临床前研究中表明，通过对我们的“PET/[18F]FU+EU”技术获得的数据进行数学建模，可以精确测量FU的细胞摄取和合成代谢。拟议研究的具体目的是：(1)评估我们的“PET[18F]FU+EU”技术预测肿瘤对一种治疗形式的反应，该技术与之密切相关，即由EU调节的FU（“FU+EU”）；(2)在更大的结肠癌患者群体中重复海德堡研究“PET/[18F]FU”。目前FU+EU的II期临床试验以及FU分解代谢作为肿瘤耐药机制的重要性的新适应症增强了Aim 1的及时性。虽然PET和[18F]FU可能提供与胸苷酸合成酶（TS）相关的信息，TS是FU的主要靶点，但成像技术并不能直接测量TS的抑制作用。在拟议的研究中，肿瘤中的TS浓度，已知与肿瘤反应相关，将在治疗前通过肿瘤活检来测量。多元回归分析将用于评估从PET和离体TS试验中获得的参数组合作为肿瘤反应的预测因子。

There is a substantial need to develop accurate methods for predicting individual response to chemotherapy. Imaging of radiolabeled chemotherapeutic drugs with PET provides one approach to this problem. However, the usefulness of PET with drugs that are rapidly broken down in vivo, such as 5-fluorouracil (FU), is limited by the inability of the methodology to directly identify the molecular association of the radiolabel. Our long range objective is to develop PET as a tool for predicting response to chemotherapy and individualizing regimens for treating neoplastic disease. Our intermediate range objective is to develop clinically-practical PET techniques for predicting tumor response to FU. In order to be effective, FU must be taken up by tumor cells and anabolized to fluoronucleotides, which in turn interfere with DNA and RNA synthesis. Investigators at Heidelberg, Germany, recently reported positive correlation between tumor response to FU and tumor retention of radiolabel from [18F]FU as measured in PET in 17 patients undergoing treatment for metastatic colon cancer. While very promising, this study did not address the influence of recirculating, labeled catabolites of [18F]FU on the PET images, and the imaging technique used provides little information about the kinetics of FU in tumors. We are developing a new approach in which biomodulation is used to create an in vivo imaging technique capable of measuring tumor transport and metabolism of FU per se. Specifically, we pretreat with ethynyluracil (EU), a potent inhibitor of FU catabolism, to prevent degradation of [18F]FU and thereby improve the sensitivity of PET to those aspects of FU pharmacokinetics most closely related to tumor response. We have shown in preclinical studies with a rat colon tumor model that cellular uptake and anabolism of FU can be accurately measured by mathematical modeling of data obtained with our "PET/[18F]FU+EU"technique. The specific aims of the proposed study are (1) to evaluate our "PET[18F]FU+EU" technique for predicting tumor response to a form of therapy in which the technique is very closely related, viz., FU modulated by EU ("FU+EU"); and (2) to repeat the Heidelberg study "PET/[18F]FU") in a larger group of patients with colon cancer. The timeliness of Aim 1 is enhanced by current Phase II clinical trials of FU+EU and new indications of the importance of FU catabolism as a mechanism of tumor resistance to the drug. While PET and [18F]FU may provide information related to thymidylate synthase (TS), the primary target of FU, the imaging techniques does not measure TS inhibition directly. In the proposed study, TS concentration in tumor, a known correlate of tumor response, will be measured via tumor biopsy prior to therapy. Multiple regression analysis will be used to evaluate combination of parameters derived from PET and ex vivo TS assays as predictors of tumor response.