Molecular Correlates--Oxaliplatin/5FU/XRT, Esophageal CA

分子相关性--奥沙利铂/5FU/XRT，食管CA

• 批准号: 6339963
• 负责人: LAKSHMI PENDYALA
• 金额: $ 31.66万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6339963
• 关键词: DNA repair; antineoplastics; clinical trial phase I; combination cancer therapy; combination chemotherapy; drug administration rate /duration; enzyme activity; esophagus neoplasm; fluorouracil; gene induction /repression; human subject; human therapy evaluation; multidrug resistance; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer radiation therapy; oxidoreductase; patient oriented research; pharmacokinetics; platinum; polymerase chain reaction; protein glutamine gamma glutamyltransferase; thymidylate synthase

DESCRIPTION (Provided by applicant): There is a pressing need for new agents in the treatment of esophageal cancer and to identify intratumoral molecular markers predictive for tumor response to chemotherapy. Although cisplatin/5-fluorouracil (5FU) plus radiation (XRT) is considered standard therapy for patients with locally advanced esophageal cancer, distant tumor recurrence, representing chemotherapy failure, is the rule. Moreover, the toxicity profile for cisplatin may be disabling. Oxaliplatin (OXP) a diaminocyclohexane platinum complex has a more manageable toxicity profile. Clinical/pre-clinical data suggest OXP-5FU synergy; mechanisms behind the synergy are not understood. Prior studies have shown that response and survival after therapy with 5FU (colon cancer) or 5FU/cisplatin (gastric cancer) are inversely associated with thymidylate synthase (TS), dihydropyrmidine dehydrogenase (DPD) and the excision repair cross-complementing-1 (ERCC-1) gene expressions. Studies of OXP resistant cell lines indicate that resistance is multifactorial, as evidenced by lowered drug accumulation, increased glutathione and decreased DNA-Pt adducts. Resistant cells also had elevated expression of gamma-glutamyltranspeptidase (gamma-GT) and ERCC- 1 genes. Thus, the underlying hypotheses in this application are: A) molecular markers within a primary esophageal tumor will predict sensitivity or resistance to chemotherapy, B) oxaliplatin affects 5FU by lowering TS gene expression and C) pharmacokinetics (PK) of OXP will influence the changes in gene expression. The specific aims of this study are to determine: 1) the intra-tumoral mRNA expression of TS, DPD, gamma-glutamylcysteine synthetase (gamma-GCS), gamma-GT, multidrug resistance associated protein-2 (MRP-2), ERCC-1 and xeroderma pigmentosum A (XPA) at pretreatment, 1 week after OXP alone, and after 1 cycle (with 5FU/radiation), exploring the relationship between these expression levels and response/resistance to treatment; 2) the PK of ultrafilterable platinum on day 1 when OXP is given alone and again on day 15 a week after combination with 5FU + XRT and 3) the relation between PK and changes in intratumoral gene expression and 4) maximum tolerated dose (MTD), dose limiting toxicity (DLT), and the potential therapeutic responses to OXP when given with continuous infusion 5FU + XRT. The gene expression studies will be carried out using real time quantitative RT-PCR (Taqman( r )) assays in endoscopic biopsies. Preliminary results indicate that the regimen is tolerable, the proposed gene expression measurements can be carried out using endoscopic biopsies and changes in gene expression are being detected for some genes during therapy. The long term objectives are to identify a drug combination for better clinical outcome and to identify molecular parameters predictive for response or resistance.

描述(申请人提供)：在中国急需新的代理商 食道癌的治疗及肿瘤内分子的确定 预测肿瘤对化疗反应的标志物。虽然 顺铂/5-氟尿嘧啶(5FU)加放射治疗(XRT)被认为是标准方案 局部晚期食道癌、远处肿瘤的治疗 复发，代表着化疗失败，是规则。此外， 顺铂的毒性特征可能正在失效。奥沙利铂(OXP) 二氨基环己烷铂络合物的毒性更易处理。 临床/临床前数据表明OXP-5FU具有协同作用； 协同效应是不被理解的。先前的研究表明，反应和存活率 用5FU(结肠癌)或5FU/顺铂(胃癌)治疗后 与胸苷合成酶(TS)、二氢嘧啶呈负相关 脱氢酶(DPD)与切除修复交叉互补1(ERCC-1)基因 表情。对OXP抗性细胞系的研究表明，耐药性是 多因素，如药物积累减少所证明的那样，增加了 谷胱甘肽和DNA-铂加合物减少。耐药细胞也升高了 γ-谷氨酰转肽酶和ERCC-1基因的表达。因此， 本申请中的基本假设是：a)在 食道原发肿瘤可预示对药物的敏感性或耐药性 化疗，B)奥沙利铂通过降低TS基因表达和C)影响5FU OXP的药代动力学(PK)会影响基因表达的变化。这个 本研究的具体目的是确定：1)肿瘤内的信使核糖核酸 TS、DPD、γ-谷氨酰半胱氨酸合成酶、γ-GT、 多药耐药相关蛋白-2、ERCC-1与干皮病 治疗前、单纯OXP后1周和1个周期后的色素A(XPA) (5FU/辐射)，探索这些表达之间的关系 水平和对治疗的反应/抵抗；2)超滤的PK 单独服用OXP的第一天给铂，一周后的第15天再次给药 与5FU+XRT相结合；3)PK与脑缺血变化的关系 肿瘤内基因表达和4)最大耐受剂量(MTD)，剂量限制 毒性(DLT)，以及口服避孕药的潜在治疗反应 持续输注5FU+XRT。将进行基因表达研究 实时定量RT-PCR(Taqman(R))检测在内窥镜检查中的应用 活组织检查。初步结果表明，该方案是可耐受的， 建议的基因表达测量可以使用内窥镜进行 一些基因的活组织检查和基因表达的变化正在被检测到 在治疗期间。长期目标是确定一种用于治疗的药物组合 更好的临床结果，并确定预测 反应或抵抗。