臺灣博碩士論文加值系統

Cisplatin及carboplatin，是目前使用最廣泛的化學治療藥物，常見副作用包括噁心嘔吐、骨髓抑制、神經毒性及腎毒性，特別是腎毒性約在10-30%病人身上發生，成為使用此類藥物的主要限制因素。Cisplatin及carboplatin轉變成腎毒性物質過程是先由glutathione S-transferases Pi 1 (GSTP1)酵素作用形成platinum-glutathione結合物，再經gamma-glutamyl transpeptidase及cysteine S-conjugate beta-lyase活化成帶有反應性硫基分子，此反應性硫基可接續引起對腎細胞之傷害。人類GSTP1酵素目前已被發現4種基因多型性，催化cisplatin及carboplatin能力以*C型最高、*B型次之、*A型最低。本研究擬探討台灣族群的GSTP1基因多型性與使用cisplatin及carboplatin引起腎毒性之關連性，並尋找其他可能影響腎毒性的危險因子。本研究一共納入107位接受cisplatin或carboplatin治療病人，以PCR-RFLP及allele-specific PCR檢測GSTP1 A313G和C341T多型性。結果發現在男性中帶有GSTP1 A313G變異者出現腎毒性風險較野生型(A/A)有明顯升高(OR = 3.71, 95% CI = 1.075 – 12.77, p = 0.038)，但在全體或女性病人則無此差異。另外在全體病人中，有腎毒性組接受cisplatin或carboplatin累積給藥次數比無腎毒性組明顯較高(5.20 ± 2.19 vs. 4.09 ± 1.54次, p = 0.009)，亦有較高比例之病人接受cisplatin累積劑量超過400 mg/m2 (25 vs. 5.4%, p = 0.039)。本研究顯示男性且帶有GSTP1 A313G變異、cisplatin或carboplatin累積治療次數及cisplatin累積劑量超過400 mg/m2可能為發生腎毒性之危險因子。未來應進一步研究帶有GSTP1變異對此腎毒性之差異，及其他可能影響腎毒性因素，以期給病人更安全而有效的治療方法。

Background and aims: Cisplatin and carboplatin induced nephrotoxicity is a major dose-limiting factor for platinum-based treatments. Glutathione S-transferase Pi (GSTP) catalyzes the glutathione-conjugation as the first and the key step of nephrotoxin formation from platinum. Four functionally different polymorphisms of human GSTP, differed by A→G at 313 and C→T at 341, have been identified. Carrying A→G variation at 313 may cause higher catalytic efficacy for platinum than the wild-type does. The purpose of this study was to investigate the related risk factors and the association between the polymorphism of GSTP1 and this nephrotoxicity in Taiwanese population.
Methods: In this retrospective observational study, 107 Taiwanese patients who had received cisplatin or carboplatin more than twice at Wan Fang Hospital were enrolled. These patients’ serum creatinine (Scr) and creatinine clearance (Clcr) data were collected to evaluate the occurance of nephrotoxicity. Genomic DNA isolated from peripheral blood sample was genotyped for GSTP1 A313G and C341T polymorphism by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele-specific PCR, respectively.
Results: The patients carrying variant G allele at 313 (A/G + G/G) had higher risk of nephrotoxicity than the wild-type, but there was no significant difference (OR = 2.00, 95%CI = 0.749 - 5.338, p = 0.166). In male, however, those carrying G allele had significantly higher risk of nephrotoxicity (OR = 3.71, 95%CI = 1.075 – 12.77, p = 0.038). Additionally, the patients with nephrotoxicity received significantly more cycles of cisplatin or carboplatin (5.20 ± 2.19 vs. 4.09 ± 1.54 times, p = 0.009). It was also observed that there was a higher ratio of the patients received cumulative dose of cisplatin > 400 mg/m2 in the nephrotoxicity group (25 vs. 5.4%, p = 0.039).
Conclusion: The results suggest that male patients with G allele, the more cycles of administration and the cumulative dose of cisplatin > 400 mg/m2 might be the risk factors of nephrotoxicity. Further studies are warranted to clarify the role of GSTP1 polymorphism in this nephrotoxicity or the interaction between GSTP1 polymorphism and other risk factors.

第1章 緒論 1
第2章 文獻探討 2
2.1 Cisplatin及carboplatin簡介 2
2.1.1 Cisplatin及carboplatin之化學結構和作用機轉 2
2.1.2 Cisplatin及carboplatin之藥物動力學 4
2.1.3 Cisplatin及carboplatin之使用療程 5
2.1.4 Cisplatin及carboplatin除腎毒性外常見副作用 5
2.2 Cisplatin及carboplatin之腎毒性 7
2.2.1 Cisplatin及carboplatin之腎毒性 7
2.2.2 Cisplatin及carboplatin腎毒性之危險因子 10
2.2.3 腎毒性預防措施 12
2.3 Cisplatin及carboplatin副作用與基因多型性之關連 12
2.3.1 運輸蛋白多型性 13
2.3.2 去活性化酵素多型性 14
2.3.3 DNA修復酵素多型性 14
2.4 Glutathione S-transferases(GST)酵素 15
2.4.1 GST酵素Pi(π)亞型 16
2.4.2 GSTP基因多型性 17
2.4.3 GSTP基因多型性與Cisplatin及carboplatin之腎毒性 21
第3章 研究目的 22
第4章 研究方法 23
4.1 研究設計 23
4.1.1 病患描述 23
4.1.2 病歷資料收集 24
4.1.3 研究相關定義 24
4.2 基因型檢測 25
4.2.1 DNA萃取 26
4.2.2 聚合?○s鎖反應-限制?﹞螺峇軉q長度多型性(PCR-RFLP) 26
4.2.3 聚合?○s鎖反應-對偶基因特性聚合?○s鎖反應(PCR-Allele-specific PCR) 28
4.2.4 製備質體(Plasmid)DNA 29
4.2.5 基因型判定 31
4.3 統計方法 33
第5章 研究結果 34
5.1 基本資料分析 34
5.2 GSTP1基因分析 36
5.2.1 Hardy-Weinberg平衡 36
5.2.2 GSTP1基因分佈 36
5.3 GSTP1基因型與腎毒性關連分析 38
5.3.1 GSTP1基因型與腎毒性關連之性別差異 39
5.4 給藥因子與腎毒性關連分析 40
5.4.1 累積劑量與腎毒性關連分析 40
5.4.2 累積給藥強度與腎毒性關連分析 41
第6章 討論 42
6.1 研究結果討論 43
6.1.1 GSTP1對偶基因與基因型頻率分佈比較 43
6.1.2 GSTP1基因多型性與腎毒性之關連 45
6.1.3 其他腎毒性危險因子 48
6.2 研究限制與未來改進方向 51
第7章 結論 53
參考文獻 54

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