鄭安理2006-07-262018-07-112006-07-262018-07-111999http://ntur.lib.ntu.edu.tw//handle/246246/23399「細胞凋亡」(apoptosis)是化學治療藥 物引發癌細胞死亡之主要機制。Bcl-2 與 Bax 是主宰細胞凋亡的兩個重要基因。 Bcl-2 蛋白的表現，可「抵抗」細胞凋亡； 相反的，Bax 則可「促進」細胞凋亡。過去 幾年來，我們一直致力於提昇胃癌化療的 成績，並闡明胃癌細胞產生抗藥性的原 因，在本研究中，我們進一步探討Bcl-2/Bax 在胃癌的化學治療抗藥性中所扮演的角色。臨床化療反應與組織染色之關聯研究: 運用免疫組織化學染色法進行29 位胃癌病 患胃癌組織之Bcl-2 與Bax 蛋白表現之測 定，再與化學治療反應進行關聯性分析。 其中分別有3 位與21 位胃癌病患組織有 Bcl-2 與Bax 蛋白表現(分別佔10.3 ± 5.7% 與72.4 ± 8.3%)，但與胃癌化學治療反應並 無統計上有意義之關聯(P 值分別為0.078與0.943)。胃癌細胞株研究:以Bcl-2 轉殖進入原 先並無Bcl-2 表現之胃癌細胞株(AGS; NCI-N87)中，取得Bcl-2 之穩定轉殖株，再 比較轉殖前後細胞株各種抗癌藥物IC50 之 變化。發現Bcl-2 的”高度表現”可造成胃癌 細胞全面多重藥物抗藥性。此種Bcl-2 轉殖 胃癌細胞株將可作為未來”篩選”「反轉Bcl-2 抗藥性藥劑」之體外研究模式。結論:本研究結果顯示Bax 在胃癌組 織中之表現較Bcl-2 常見，但在臨床化療反 應與組織染色之關聯研究中，兩者與胃癌 化學治療反應均未達統計上有意義之關聯。然而，在胃癌細胞株研究中，Bcl-2 的” 高度表現”顯示與胃癌細胞之化學藥物全 面抗藥性相關。這些結果有助於了解胃癌 細胞之抗藥性及抗凋亡性，作為將來提昇 胃癌化療效果之參考依據。“ Apoptosis ” is the final common path-way of most chemotherapy-induced tumor cell death. Bcl-2 and Bax are two of the key players regulating the apoptosis phenomenon. Bcl-2 is a blocker of apoptosis, while Bax functions as a promoter of apoptosis. In this study, we examined the roles of Bcl-2 and Bax in drug resistance of gastric cancer cells. Bcl-2 and Bax protein expression were determined by immunohistochemical stains in 29 gastric cancer tissues, and correlated with chemotherapy responses (13 responders and 16 non-responders). Bcl-2 and Bax protein expression was found in 10.3 ± 5.7% and 72.4 ± 8.3% gastric cancer tissues, respectively. However, In this group of patients, we cannot find statistically significant correlation between Bcl-2 or Bax protein expression and chemotherapy responses (P= 0.078 and 0.943 by Fisher exact test, respectively). In cell line studies, we have examined 7 human gastric cancer cell lines. All of them had Bax expression, and 5 of them had Bcl-2 expression (except AGS and NCI-N87). These two Bcl-2(-) parental gastric cancer lines were transfected with Bcl-2 cDNA expression vector, selected for stably trans-fected clones, verified by Western blot, then selected for further study. Compared with the parental cell lines, the Bcl-2 transfectants had 1.7- to 125-fold higher IC50 of multiple structurally unrelated chemotherapeutic agents, including 5-FU, cisplatin, doxo-rubicin, etoposide, paclitaxel, and docetaxel. We concluded that (1) Bax protein is more frequently expressed than Bcl-2 in gastric cancer tissues; (2) although we cannot find statistically significant correlation between Bcl-2 or Baxprotein expression and HDFL-based chemotherapy responses, our in vitro cell line model suggests that Bcl-2 overexpression may be a multidrug resistance marker of gastric cancer. This in vitro model is potentially useful for searching of Bcl-2 modulating agents, which may help reverse drug resistance conferred by Bcl-2 overexpression.application/pdf57219 bytesapplication/pdfzh-TW國立臺灣大學醫學院內科Bcl-2Bax胃癌化療抗藥性細胞凋亡gastric cancerdrug resistanceapoptosis[SDGs]SDG3reporthttp://ntur.lib.ntu.edu.tw/bitstream/246246/23399/1/882314B002052.pdf