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（由申请人提供）： 迫切需要新的药物 食管癌的治疗并鉴定瘤内分子 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 (XRT) 被认为是标准疗法 局部晚期食管癌、远处肿瘤患者的治疗 复发代表化疗失败，这是常态。此外， 顺铂的毒性可能会导致失能。奥沙利铂 (OXP) a 二氨基环己烷铂络合物具有更易于控制的毒性特征。 临床/临床前数据表明 OXP-5FU 具有协同作用；背后的机制 协同作用不被理解。先前的研究表明，反应和生存 5FU（结肠癌）或 5FU/顺铂（胃癌）治疗后 与胸苷酸合酶 (TS)、二氢嘧啶呈负相关 脱氢酶 (DPD) 和切除修复交叉互补 1 (ERCC-1) 基因 表达式。对 OXP 耐药细胞系的研究表明，耐药性是 多因素，如药物蓄积降低所证明的， 谷胱甘肽和 DNA-Pt 加合物减少。耐药细胞也升高 γ-谷氨酰转肽酶 (γ-GT) 和 ERCC-1 基因的表达。因此， 本申请的基本假设是：A) 内的分子标记 原发性食管肿瘤将预测对药物的敏感性或耐药性 化疗，B) 奥沙利铂通过降低 TS 基因表达来影响 5FU，C) OXP的药代动力学（PK）会影响基因表达的变化。这 本研究的具体目的是确定：1​​）肿瘤内 mRNA TS、DPD、γ-谷氨酰半胱氨酸合成酶 (γ-GCS)、γ-GT 的表达， 多药耐药相关蛋白 2 (MRP-2)、ERCC-1 和干皮病 预处理时、单独 OXP 后 1 周以及 1 个周期后 （用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 单独给予 OXP 时，在第 1 天进行铂金治疗，并在一周后的第 15 天再次进行铂金治疗 与 5FU + XRT 组合以及 3) PK 与变化之间的关系 瘤内基因表达和4）最大耐受剂量（MTD），剂量限制 毒性（DLT），以及给予 OXP 时的潜在治疗反应 持续输注5FU+XRT。将进行基因表达研究 在内窥镜下使用实时定量 RT-PCR (Taqman( r )) 检测 活检。初步结果表明，该方案是可以耐受的， 提议的基因表达测量可以使用内窥镜进行 正在检测某些基因的活检和基因表达变化 治疗期间。长期目标是确定药物组合 更好的临床结果并确定预测的分子参数 反应或抵抗。