台灣地區大腸直腸癌病患之抗癌藥物相關基因多型性分析

Prevalence of Chemotherapeutic Agents-related Genetic polymorphisms in Taiwanese Patients with Colorectal Cancer

方偉宇(Wei-Yu Fang)

指導教授 ： 林綉茹

高雄醫學大學/醫學院/醫學遺傳學研究所/碩士(2007年)

https://doi.org/10.6832/KMU.2007.00109

摘要

不同種族間對於藥物的療效以及毒性都不盡相同，近年來許多研究也發現，個人間的基因差異會對用藥的質與量產生不同影響，因此本研究探討了八個基因多型性在台灣地區大腸直腸癌患者中的分佈情形並與其他種族比較，來探討是否因為基因型的頻率有差異才導致此現象。這八個基因多型性分別會影響三種大腸直腸癌化療藥物之藥物相關代謝機轉、藥物標的活性以及藥物抵抗性，而這三種化療藥物為：5-FU、Irinotecan(CPT-11)和Oxaliplatin。在藥物相關代謝機轉中，吾人探討了DPYD、MDR1、UGT1A1、GSTP1這四種基因；在藥物標的活性方面，選擇了5-FU的藥物標的基因，TS；另外再加上5-FU藥物作用的輔因子，MTHFR；在藥物抵抗性方面，則探討了有關DNA修復系統的基因，包括有XRCC1以及XPD。吾人利用聚合酶連鎖反應結合限制酶切割片段長度多型性分析(PCR-RFLP)更進一步以去氧核醣核酸定序此方法，來分析這八個基因多型性在台灣地區201位大腸直腸癌病患中的分佈情形。這些基因多型性的分佈頻率(%)分別為，TS(3R/3R：66.8、3R/2R：29.7、2R/2R：3.5)；MTHFR C677T(CC：60.9、CT：35.6、TT：3.5)；DPYD IVS14+ 1G>A(GG：100)；UGT1A1 TA repeat(6/6：76.2、6/7：23.8、7/7：0 )；MDR1 C3435T(CC：34.6、CT：52.0、TT：13.4)；XRCC1 Arg399Gln(Arg/Arg：61.9、Arg/Gln：31.7、Gln/Gln：6.4)；XPD Lys751Gln(Lys/Lys：87.6、Lys/Gln：11.9、Gln/Gln：0.5)；GSTP1 Ile105Val (Ile/Ile：64.3、Ile/Val：32.7、Val/Val：3.0)。與其他國家比較後發現，這些基因多型性的分佈情形在台灣地區族群與高加索人中是有所差異的，這個結果或許可解釋此不同種族對於藥物的療效及毒性不同。此研究結果也可提供台灣地區大腸直腸癌患者化療相關基因型之分子流行病學探討，並作為未來基因型相關研究之參考。

關鍵字

大腸直腸癌 ； 5-氟尿嘧啶 ； 抗癌妥 ； 奧沙利鉑 ； 基因多型性 ； 藥物基因體學

並列摘要

Different drug response and toxicity were found between different races and countries. Recently, many researches have found that the different genotypes from person to person may affect drug responsiveness. In this study, we investigated eight functional genetic polymorphisms which are related to three chemotherapy agents for colorectal cancer(CRC), 5-FU, irinotecan(CPT-11), and oxaliplatin involving in drug target, metabolic pathway and DNA repair systems. Our aim was to analyze the prevalence of these genetic polymorphisms in CRC patients in Taiwan and compare with other races. Genotyping of metabolizing genes dihdropyrimidine dehydrogenase(DPYD), uridine diphosphate glucuronosyltransferase(UGT1A1), multidrug resistance 1(MDR1), glutathione S-transferase P1(GSTP1), DNA repair genes X-ray cross-complementing 1(XRCC1) and xeroderma pigmentosum group D(XPD), drug target gene thymidylate synthase(TS), and co-factor gene methylenetetrahydrofolate reductase(MTHFR) were performed in 201 CRC patients using a polymerase chain reaction restriction fragment length polymorphism(PCR-RFLP) technique and DNA sequencing. Results: The frequencies of 3R/3R, 3R/2R, and 2R/2R genotypes of TS polymorphism were 67.2%, 29.3%, and 3.5%; the frequencies of CC, CT, and TT genotypes of MTHFR C677T polymorphism were 60.7%, 35.8%, 3.5%, respectively; the frequencies of GG genotypes of DPYD IVS14 + 1G>A polymorphism were 100%, and no patients with mutations; the frequencies of 6/6 and 6/7 genotypes of UGT1A1 TA repeats were 76.1% and 23.9%, respectively; the frequencies of CC, CT, and TT genotypes of MDR1 C3435T were 34.8%, 51.8%, and 13.4%; the frequencies of Arg/Arg, Arg/Gln, Gln/Gln genotypes of XRCC1 Arg399Gln were 61.7%, 31.8%, and 6.5%, respectively; the frequencies of Lys/Lys, Lys/Gln, Gln/Gln genotypes of XPD Lys751Gln were 87.6%, 11.9%, and 0.5%; the frequencies of Ile/Ile, Ile/Val, Val/Val genotypes of GSTP1 Ile105Val polymorphism were 64.2%, 32.8%, and 3.0%, respectively. The present study showed that these variants frequencies were similar to frequencies observed in other oriental populations but have difference between Taiwanese and Caucasian. The results may explain the different drug response and toxicity between different races and offer an epidemiological discussion and can be a reference of relevant research in the future.

並列關鍵字

colorectal cancer ； 5-FU ； irinotecan (CPT-11) ； oxaliplatin ； polymorphism ； Pharmacogenomics

參考文獻

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