RESPONSE DETERMINANTS IN ESOPHAGEAL AND GASTRIC CANCERS

根据越来越多的数据，人们推测， 特定的肿瘤内酶影响特定的 化疗药物。利用聚合酶链式反应(PCR) 技术和放射性配基结合分析，该项目将尝试 为了确定肿瘤内的基因表达水平和 5-氟尿嘧啶(5FU)靶标酶的蛋白质定量 胸苷酸合酶(TS)影响联合反应 化疗，和/或这些水平在治疗期间和治疗后是否发生变化 治疗。同时对肿瘤内减少的叶酸池进行检测 时间作为TS确定以确定这些水平是否会影响 在治疗过程中也有反应或变化。原发疾病的患者 胃癌和食道癌的术前治疗 化疗。为了分离顺铂对叶酸库减少的影响， 每个方案的化疗都将使用大剂量顺铂 长期输注5FU+亚叶酸钙1周。对病人来说 随着食道癌的增加，放射治疗将与第一周期 长期输注5FU。在新辅助治疗之后，手术将 手术切除原发癌。通过测量基因和蛋白质 TS和减少的叶酸池在食道和胃中的表达 肿瘤在这些时间间隔该项目将定义是否水平 肿瘤内TS和叶酸池减少影响治疗或 通过治疗来改变。这样的关联将导致更好的 对先天和获得性肿瘤耐药的理解 加强对恶性肿瘤的合理治疗设计。最终， 新辅助和术后辅助治疗可个体化 根据肿瘤是否具有先天抵抗力，获得抵抗力 或者尽管进行了密集的术前治疗，但仍保持敏感。

Based on a growing body of data, it has been postulated that levels of specific intratumoral enzymes influence the action of particular chemotherapeutic agents. Using polymerase chain reaction (PCR) technology, and a radioligand binding assay, this project will attempt to determine whether the intratumoral level of gene expression and the quantitation of protein for the 5-fluorouracil (5FU) target enzyme thymidylate synthase (TS) influences response to combination chemotherapy, and/or whether these levels change during and after treatment. Intratumoral reduced folate pools will be assayed at the same time as the TS determinations to ascertain if these levels affect response or change during treatment as well. Patients with primary gastric and esophageal cancers will be treated with preoperative chemotherapy. To isolate cisplatin's effect on reduced folate pools, the chemotherapy in each program will employ high dose cisplatin followed in one week by a protracted-infusion of 5FU with leucovorin. For patients with esophageal cancer radiation will be added with the first cycle of protracted-infusion 5FU. Following neoadjuvant therapy an operation will be done to remove the primary cancer. By measuring gene and protein expression of TS and reduced folate pools within esophageal and gastric neoplasms at these intervals this project will define whether levels of intratumoral TS and reduced folate pools affect response to therapy or change with therapy. Such correlations will lead to a better understanding of innate and acquired tumor resistance in these malignancies and enhance rational treatment design. Eventually, neoadjuvant and postoperative adjuvant treatments may be individualized on the basis of whether tumors are innately resistant, acquire resistance or remain sensitive despite this intensive preoperative therapy.