PREDICTING TUMOR RESPONSE TO FLUOROURACIL WITH PET

存在开发用于预测个体对化疗的反应的准确方法的实质性需要。放射性标记的化疗药物与PET成像提供了一种方法来解决这个问题。然而，PET与在体内快速分解的药物（如5-氟尿嘧啶（FU））的有效性受到无法直接识别放射性标记分子缔合的方法的限制。我们的长期目标是开发PET作为预测化疗反应和治疗肿瘤疾病的个体化方案的工具。我们的中期目标是开发临床实用的PET技术，用于预测肿瘤对FU的反应。为了有效，FU必须被肿瘤细胞吸收并合成代谢为荧光素，荧光素反过来又干扰DNA和RNA的合成。德国海德堡的研究人员最近报告了在17例接受转移性结肠癌治疗的患者中，通过PET测量，肿瘤对FU的反应与[18 F]FU放射性标记的肿瘤保留之间呈正相关。虽然非常有前景，但该研究并未解决[18 F]FU的再循环标记催化剂对PET图像的影响，并且所使用的成像技术几乎没有提供有关肿瘤中FU动力学的信息。我们正在开发一种新的方法，其中使用生物调节来创建能够测量肿瘤转运和FU本身代谢的体内成像技术。具体而言，我们用一种有效的FU催化剂抑制剂乙炔尿嘧啶（EU）进行预处理，以防止[18 F]FU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。我们已经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/[18 F]FU+EU“技术获得的数据进行数学建模，可以准确测量FU的细胞摄取和抑制。拟议研究的具体目的是（1）评价我们的“PET[18 F]FU+EU”技术用于预测肿瘤对一种治疗形式的反应，其中该技术非常密切相关，即，EU调节的FU（“FU+EU”）;和（2）在更大的结肠癌患者组中重复海德堡研究“PET/[18 F]FU”）。目前的FU+EU II期临床试验和FU催化剂作为肿瘤耐药机制的重要性的新适应症增强了目标1的及时性。虽然PET和[18 F]FU可以提供与胸苷酸合成酶（TS）（FU的主要靶点）相关的信息，但成像技术不能直接测量TS抑制。在拟定的研究中，肿瘤中的TS浓度（已知与肿瘤缓解相关）将在治疗前通过肿瘤活检进行测量。将使用多元回归分析来评价PET和离体TS测定的参数组合作为肿瘤缓解的预测因子。

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.