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

描述（由申请人提供）：迫切需要新的代理商， 食管癌的治疗和肿瘤内分子鉴定 预测肿瘤对化疗反应的标志物。虽然 顺铂/5-氟尿嘧啶（5 FU）加放疗（XRT）被认为是标准治疗 局部晚期食管癌、远处转移癌 复发，代表化疗失败，是规律。而且 顺铂的毒性特征可能是致残性的。奥沙利铂（OXP）a 二氨基环己烷铂络合物具有更易控制的毒性特征。 临床/临床前数据表明OXP-5 FU协同作用; 协同作用不被理解。先前的研究表明， 在用5 FU（结肠癌）或5 FU/顺铂（胃癌）治疗后， 与胸苷酸合成酶（TS）、二氢嘧啶 脱氢酶（DPD）和切除修复交叉互补基因（ERCC-1） 表情对OXP抗性细胞系的研究表明， 多因素，如药物蓄积降低所证明的， 谷胱甘肽和减少的DNA-Pt加合物。耐药细胞也有升高 γ-谷氨酰转肽酶（γ-GT）和ERCC- 1基因的表达。因此，在本发明中， 本申请中的基本假设是：A）分子标记物， 原发性食管肿瘤将预测对 B）奥沙利铂通过降低TS基因表达影响5 FU，和C） OXP的药代动力学（PK）将影响基因表达的变化。的 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、 多药耐药相关蛋白-2（MRP-2）、ERCC-1与干皮病 治疗前、OXP单独给药后1周和1个周期后的色素瘤A（XPA） (with 5 FU/放疗），探讨这些表达与肿瘤细胞凋亡的关系。 水平和对治疗的反应/抵抗力; 2）超滤的PK 当OXP单独给药时，第1天给予铂，一周后第15天再次给予铂 与5 FU + XRT联合治疗之间的关系，以及3）PK与 肿瘤内基因表达和4）最大耐受剂量（MTD），剂量限制 毒性（DLT），以及与OXP联合给药时对OXP的潜在治疗反应 连续输注5 FU + XRT。将进行基因表达研究 在内窥镜检查中使用真实的时间定量RT-PCR（Taqman（r））测定 活组织检查初步结果表明，该方案是可以耐受的， 所提出的基因表达测量可以使用内窥镜 一些基因的活组织检查和基因表达的变化正在被检测出来 在治疗期间。长期目标是确定一种药物组合， 更好的临床结果，并确定分子参数预测 反应或抵抗。

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.