本文選題：肺腺癌 + 胸苷酸合成酶TYMS�。� 參考：《大連醫(yī)科大學(xué)》2017年碩士論文

【摘要】：目的:培美曲塞(pemetrexed,PEM)于2004年首次被美國食品與藥品管理局(food and drug administration,FDA)批準(zhǔn)為治療惡性胸膜間皮瘤的臨床一線化療藥。隨后的研究表明培美曲塞在治療晚期非鱗狀非小細(xì)胞肺癌,可同樣使患者受益。培美曲塞作為一類多靶點的化療藥物,能夠明顯降低胸苷酸合成酶(Thymidylate synthase,TS)、二氫葉酸還原酶(Dihydrofolate reductase,DHFR)及甘氨酸胺核苷酸甲酰基轉(zhuǎn)移酶(Glycinamide ribonucleotide formyl transferase,GARFT)等細(xì)胞合成代謝相關(guān)酶的活性,從而達(dá)到降低腫瘤細(xì)胞惡性增殖的效果。許多實驗室研究及臨床研究證據(jù)表明,TYMS作為TS的基因形式,其多態(tài)性會直接影響TS的表達(dá)水平,從而造成惡性腫瘤患者對培美曲塞的化療敏感性的不同。然而TYMS基因多態(tài)性在預(yù)測含培美曲塞化療方案治療晚期肺腺癌敏感程度的臨床價值方面仍有爭議。本研究通過對我院晚期肺腺癌患者外周血中TYMS基因的多態(tài)性分布及其與培美曲塞化療療效的關(guān)系分析,旨在了解晚期肺腺癌患者外周血TYMS基因多態(tài)性對含培美曲塞化療方案療效的指導(dǎo)意義。同時結(jié)合患者臨床資料,分析不同臨床病理參數(shù)對TYMS基因多態(tài)性及培美曲塞化療療效的影響,最終完善晚期肺腺癌患者的個體化治療模式。方法:收集大連醫(yī)科大學(xué)附屬第一醫(yī)院2010年1月1日至2015年12月31日,經(jīng)影像學(xué)及病理學(xué)明確診斷為晚期(ⅢB期及Ⅳ期)肺腺癌的患者56例。患者在化療前均采集了外周靜脈血,使用血全基因組DNA提取試劑盒(Solarbio,D1800,Beijing)提取基因組DNA,采用聚合酶鏈反應(yīng)(PCR)擴(kuò)增,利用2%瓊脂糖凝膠檢測PCR擴(kuò)增產(chǎn)物,分析TYMS基因5' UTR長度多態(tài)性。TYMS基因型結(jié)果分析分別為116 bp的2R/2R,144 bp的3R/3R以及同時包含116 bp和144 bp的2R/3R。此56例患者均接受了含培美曲塞的雙藥聯(lián)合化療方案(培美曲塞+順鉑或培美曲塞+卡鉑),3周為一周期�；熎陂g,每2周期進(jìn)行一次影像學(xué)療效評價;化療后,每2個月評價一次。隨診患者至2017年1月1日。記錄所有患者的臨床病理參數(shù),包括患2者的年齡、性別、腫瘤分期、ECOG評分、吸煙狀況及TYMS基因多態(tài)性。應(yīng)用SPSS20.0統(tǒng)計軟件分析各臨床病理參數(shù)與TYMS基因多態(tài)性及疾病控制率(disease control rate,DCR)的相關(guān)性,同時比較TYMS基因多態(tài)性和患者無進(jìn)展生存時間(progression-free survival,PFS)及總生存時間(overall survival,OS)的關(guān)系。結(jié)果:1.56例晚期肺腺癌患者年齡分布于32-80歲,中位年齡61歲;男性患者32人,女性患者24人;臨床分期ⅢB期22人,Ⅳ期34人;ECOG評分0分16人,1分31人,2分9人;吸煙者25人,不吸煙者31人。利用RECIST 1.1評分標(biāo)準(zhǔn)評分,其中完全緩解(CR)0人,部分緩解(PR)19人,病變穩(wěn)定(SD)21人,疾病進(jìn)展(PD)16人,疾病控制率DCR(CR+PR+SD)為71.43%。2.TYMS5'UTR基因多態(tài)性中,2R/3R基因型患者23例,占41.1%,3R/3R型患者19例,占33.9%,2R/2R患者14例,占25%。3.56例患者性別、年齡、臨床分期、ECOG評分及吸煙狀況與TYMS 5'UTR基因多態(tài)性之間無相關(guān)性(P0.05),研究同時顯示以上臨床病理參數(shù)與接受培美曲塞化療的肺腺癌患者DCR之間也無相關(guān)性(P0.05)。4.2R/2R+2R/3R組患者的DCR明顯優(yōu)于3R/3R組患者(P0.05),2R/2R+2R/3R 組患者 PFS 顯著長于 3R/3R 組(P0.001)。5.2R/2R+2R/3R組患者較3R/3R組的OS較長,但二者比較無統(tǒng)計學(xué)意義(P=0.10)。結(jié)論:1.晚期肺腺癌患者外周血胸苷酸合成酶TYMS基因多態(tài)性中,2R/3R及3R/3R基因型較多,2R/2R基因型較少。2.TYMS 2R/2R和2R/3R基因型患者接受培美曲塞化療的DCR較3R/3R基因型患者顯著增高,PFS較3R/3R基因型患者顯著延長。3.TYMS 2R/2R和2R/3R基因型患者接受培美曲塞化療的OS較3R/3R基因型患者延長,但二者在統(tǒng)計學(xué)無顯著差異。4.TYMS基因型可作為預(yù)測晚期肺腺癌患者培美曲塞化療療效的敏感指標(biāo)。
[Abstract]:Objective: pemetrexed (PEM) was first approved by the US Food and Drug Administration (food and drug administration, FDA) for the first line of clinical chemotherapy for the treatment of malignant pleural mesothelioma in 2004. Subsequent studies showed that pemetrexed could benefit from patients with advanced non-squamous non-small cell lung cancer as well. Pemetrexed was used as a patient. A class of multitarget chemotherapy drugs can significantly reduce the activity of Thymidylate synthase (TS), dihydrofolate reductase (Dihydrofolate reductase, DHFR) and glycine amine nucleotide Methoyl transferase (Glycinamide ribonucleotide formyl transferase, GARFT), and thus reduce the activity of metabolic related enzymes. The effect of malignant proliferation of tumor cells. Many laboratory and clinical evidence suggest that TYMS is a genetic form of TS, and its polymorphism will directly affect the level of TS expression, resulting in different sensitivity to pemetrexed chemotherapy in patients with malignant tumor. However, the polymorphism of TYMS gene is expected to be late in the treatment of pemetrexed chemotherapy. The clinical value of the sensitivity of lung adenocarcinoma is still controversial. In this study, the relationship between the polymorphism distribution of TYMS gene in peripheral blood and the effect of pemetrexed chemotherapy on the peripheral blood of patients with advanced lung adenocarcinoma was analyzed. The purpose of this study was to understand the guidance of the TYMS gene polymorphism of peripheral blood in patients with advanced lung adenocarcinoma for the therapeutic effect of pemetrexed chemotherapy. The effect of different clinicopathological parameters on TYMS gene polymorphism and pemetrexed chemotherapy was analyzed combined with the clinical data of patients. Finally, the individualized treatment mode of patients with advanced lung adenocarcinoma was perfected. Methods: the First Affiliated Hospital of Dalian Medical University was collected from January 1, 2010 to December 31, 2015 by imaging and pathology. 56 patients were diagnosed as advanced (stage III B and IV) lung adenocarcinoma. The peripheral venous blood was collected before chemotherapy, genomic DNA was extracted from the whole genome DNA Extraction Kit (Solarbio, D1800, Beijing), and polymerase chain reaction (PCR) was used to amplify and detect PCR amplification products with 2% agarose gel, and the TYMS gene 5'UTR length was analyzed. The results of polymorphic.TYMS genotype analysis were 116 BP 2R/2R, 144 BP 3R/3R, and 2R/3R. with 116 BP and 144 BP respectively. All the 56 patients received pemetrexed double drug combination chemotherapy (pemetrexed + cisplatin or pemetrexed + carboplatin), 3 weeks as one cycle. During the period of chemical treatment, an image evaluation was conducted every 2 cycles. After chemotherapy, the patients were evaluated every 2 months. The patients were followed up to January 1, 2017. The clinicopathological parameters of all patients were recorded, including age, sex, tumor staging, ECOG score, smoking status and TYMS gene polymorphism. The SPSS20.0 statistical software was used to analyze the clinical parameters and TYMS gene polymorphism and disease control rate (disease). The correlation between control rate, DCR) and the relationship between the TYMS gene polymorphism and the patient's progression free survival time (progression-free survival, PFS) and the total survival time (overall survival, OS). Results: 1.56 patients with advanced lung adenocarcinoma were aged 32-80 years, the median age was 61 years, 32 men and 24 women, and clinical stage III. Period B 22, stage IV 34; ECOG score 0 points 16 people, 1 points 31 people, 2 minutes and 9 people, 25 smokers and 31 non smokers, using the RECIST 1.1 score standard, including complete remission (CR) 0, PR 19, disease progression (PD) persons, disease control rate DCR (CR+PR+SD) as 71.43%.2.TYMS5'UTR gene polymorphism, 2R/3R basis 23, 41.1%, 19, 33.9%, and 14 2R/2R patients in 3R/3R patients, accounting for sex, age, clinical stage, ECOG score, smoking status and TYMS 5'UTR gene polymorphism (P0.05). The study also showed that the above clinical parameters were also between the DCR patients receiving pemetrexed chemotherapy and DCR of the lung adenocarcinoma patients. The DCR of patients with no correlation (P0.05).4.2R/2R+2R/3R was significantly better than that in group 3R/3R (P0.05), and PFS in group 2R/2R+2R/3R was longer than that of 3R/3R group (P0.001).5.2R/2R+2R/3R group. The OS was longer than that of 3R/3R group, but there was no significant difference between the two groups. Conclusion: the polymorphism of peripheral thymside synthase synthetase gene polymorphism in the 1. late stage lung adenocarcinoma patients In sex, the genotype of 2R/3R and 3R/3R is more, and the DCR in the 2R/2R genotype less.2.TYMS 2R/2R and 2R/3R genotype patients receiving pemetrexed chemotherapy is significantly higher than that of the 3R/3R genotype patients. PFS is significantly longer than the 3R/3R genotype patients to prolong the.3.TYMS 2R/2R and the patients receiving pemetrexed chemotherapy longer than those of the 3R/3R genotype, but two There was no significant difference between the two groups..4.TYMS genotype can be used as a sensitive indicator for predicting the efficacy of pemetrexed in advanced lung adenocarcinoma.
【學(xué)位授予單位】：大連醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R734.2
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本文編號：1994159