- 學位論文
醇去氫酶(ADH2)與醛去氫酶(ALDH2)之基因多型性與食道癌病人接受輔助化學治療後其預後之相關性研究
The relationship between polymorphisms of ADH2 and ALDH2 and the prognosis of esophageal cancer patients with adjuvant chemotherapy
摘要
食道癌初期通常沒有特別的症狀， 因此病人常常因為延遲就診造成治療上的困難。食道癌的原因以及發生率現今已有大量研究，但是治療方面對於臨床醫師依然是極大的挑戰。目前治療食道癌以手術治療為主，輔助化學治療亦佔了極重要的角色。 醇去氫酶（alcohol dehydrogenases，ADH）及醛去氫酶（aldehyde dehydrogenases，ALDH）是人體中非常重要的代謝型基因，醇去氫酶主要作用於酒精的代謝，醛去氫酶作用於乙醛的代謝。這二種酶均具有基因多型性，代謝酒精與乙醛的能力並不相同。 本研究自1999年十月至2004年十月之間，由高雄醫學大學附設醫院及高雄榮民總醫院兩間大型醫學中心共收集了229個食道癌病人，追蹤期間截至2005年六月三十一日止，紀錄病人的治療方法、存活時間、復發時間、病理分期等，收集病人血液粹取DNA，以聚合脢鍊鎖反應(polymerase chain reaction「PCR」)與限制片段長度多型性分析方法(restriction fragment length polymorphism「RFLP」),來進行ADH2和ALDH2基因型之鑑定。 將病人以手術與否以及是否接受術後化學輔助治療加以分組，以SPSS 12.0版分析所有變異項目與病人存活長短，得知不論是病人受否接受手術或化學治療，ADH2基因多型性對於病人存活並無顯著影響；ALDH2基因多型性於接受手術病人又接受術後輔助化學治療的病人，若帶有2* allele基因型的病人存活時間較短，具有顯著意義（P=0.0313） 由於化學治療藥物本身具有很高的細胞毒性，手術之後立即接受術後輔助化學治療，會造成大量細胞死亡，細胞內醣類、脂質、蛋白質、核酸於代謝過程之中將產生許多乙醛作為中間產物，因此帶有ADH2 2* allele基因型的病人，由於清除乙醛的能力較差，可能使乙醛大量堆積而造成更大的細胞毒性，進而縮短存活時間。 關鍵字：食道癌，醇去氫酶，醛去氫酶，基因多型性。
並列摘要
Abstract Objective: The esophageal cancer is a poor prognostic disease. It is always diagnosed latterly because the early symptoms are not specific. When this disease is noted, it is in advanced stage. The standard treatment of esophageal cancer is surgical resection. The adjuvant chemotherapy and radiotherapy are given for patients who are advanced stage. Material and methods: From Oct. 1999 to Oct 2004, total 229 patients with esophageal cancer are diagnosed in our hospital. Among these patients, 106 receive subtotal esophagectomy with radical lymph node dissection. All of them also receive gastric or colon tube reconstruction. The fresh blood of patients is collected. The gene analysis are made by Purgene DNA isolation kit (Gentra systems, Inc., MN). This genomic DNA will serve as a template for PCR amplification of each polymorphic gene including ADH2 and ALDH2. PCR-RFLP methods are used for detecting the gene polymorphisms. Results : All the patients are in advanced stage (TNM stage IIa and III). After surgery, the post-operative adjuvant chemotherapy and radiotherapy are given. The regular follow up of these patients are monitored. The recurrence date and mortality date are collected and disease free interval and survival days are also calculated. There are three genotypes in ADH2*1/*1, ADH2*1/*2, ADH2*2/*2; ALDH2*1/*1 ALDH2*1/*2, ALDH2*2/*2. All the data are calculated by SPSS 12.0. In the group of patients receive radical surgical intervention and post-operative chemotherapy, ALDH2 2*allele makes more shorter survival time than others.（p=0.013） Comments: Chemotherapy in post-operative stage are seen as the proper choice for adjuvant therapy after surgery, especially in the advanced stage. In long time it was thought that adjuvant chemotherapy may increase the survival time. The chemotherapeutic drugs have highly toxicity, they may cause large amount of cells death. During this period, large carbohydrate, lipid, proteins should be metabolized, then massive acetyl aldehyde will be produced as intermediate products. Because the ALDH2 *2/*2 genotype may have less ability of cleaning acetyl aldehyde than other, it will makes shorter survival time. Keywords : Alcohol and aldehyde dehydrogenases and esophageal cancer, genetic polymorphism