| Abstract: | 肺癌是全世界致死率最高的癌症。 此疾病主要分成兩大類，一為非小細胞肺癌其發生率約為85％；另一類為小細胞肺癌佔15％。 即使以最新藥物治療，肺癌病人五年的存活率仍僅為14％。 因此，研發安全有效的肺癌治療策略實為當務之急。 近年來上皮細胞生長因子受体（EGFR）被視為一重要的抗癌藥物研發之標的分子。 ZD1839是一quinazoline的衍生物，可選擇性的抑制上皮細胞生長因子受体的酪胺酸激活性，目前此藥已臨床應用於治療癌症病人。 我們在臨床研究探討肺癌末期且體力很差病人，服用ZD1839藥物之容忍性及有效性。 結果發現有效反應率達25％，平均存活率2.5個月。 顯示ZD1839可有效應用於台灣肺癌末期之病人，其效果較歐洲及美洲人更好。 且未使用化療藥物者服用ZD1839之療效較曾經使用過化療藥物者佳。 同時我們發現服用ZD1839的病人會有甲溝炎及膚色暗沈之副作用。 本論文進一步用培養的人類肺腺癌A549細胞探討ZD1839抗癌作用之分子機轉。 結果發現處理ZD1839可使A549細胞生長停滯於細胞週期G1期，接著誘發細胞凋亡。 結果並指出ZD1839處理使細胞內Cdk-2，-4，-6及cyclin-D1及-D3分子之表現減少，而p27KIP1及pRb2/p130分子大量表現，因而造成細胞週期停於G1期。 此外，ZD1839之處理抑制ERK激活性，導致細胞死亡受体Fas蛋白表現量增加，進而啟動細胞凋亡之程式，活化caspase-8及-3，終至細胞死亡。Gemcitabine是目前臨床常用的治療肺癌藥物，但報導指出其與ZD1839併用會產生藥效拮抗之效應。 為探究其作用機轉，本研究將肺癌細胞處理Gemcitabine，發現此藥物藉由活化ERK及抑制AKT進而達到使肺癌細胞致死的效果。 且先處理Gemcitabine，接著再處理ZD1839，可使肺癌細胞凋亡之效果增強；但若先處理ZD1839接著再處理Gemcitabine，則呈現拮抗的效應，肺癌細胞死亡率顯著下降。 此結果顯示ZD1839及Gemcitabine兩藥物使用之先後順序不同，可造成明顯的藥效差異性。
Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for about 85%, while SCLC accounts for the rest 15%. In spite of new treatments, the overall five-year survival rate remains about 14% and most patients present with advanced disease. Novel therapeutic strategies to improve efficacy in accord with safety are urgently needed. Epithelial growth factor receptor (EGFR) has been proposed as a target for anticancer therapy. ZD1839 (Iressa) is a quinazoline derivative that selectively inhibits the EGFR tyrosine kinase activity and is under clinical use in cancer patients. We retrospectively evaluated the efficacy and tolerability of ZD1839 in patients with advanced NSCLC and very poor performance status (PS) in Taiwan. Tumor response rate was 25.0% (13/52). The median overall survival was 2.5 months (response group 9.1 months, stable disease 3.1 months, and progressive group 0.8 month, p < 0.001). Clinically, ZD1839 has good antitumor activity and tolerability in Taiwan patients with advanced NSCLC and very poor performance status. Taiwan patients have a higher response rate to ZD1839 than that had been seen in Europe or in European heritage Americans. Chemonaive patients responded better than patients with prior chemotherapy. We also found the unique side effects of ZD1839, inducing paronychia and skin hyperpigmentation in some of our patients. The molecular mechanisms involved in ZD1839-mediated anticancer effects were characterized using human lung adenocarcinoma A549 cells in this study,exposure of A549 cells to ZD1839 caused G1 arrest, and subsequently induced apoptosis. The results indicate that downregulation of the expression and function of CDK2, CDK4, CDK6, cyclin-D1 and cyclin-D3, as well as upregulation of p27KIP1 and pRb2/p130, both are strong candidates for the cell cycle regulator that arrests ZD1839-treated A549 cells at G1 phase. Furthermore, upregulation of Fas and inactivation of ERK appear to play a major role in the initiation of ZD1839-induced apoptosis, activation of caspase-8/caspase-3 cascade is involved in the execution phase of this death program. Gemcitabine is currently the effective chemotherapeutic drug available for patients with lung cancer, but it has minimally effective against this aggressive disease in combination with ZD1839. To understand their mode of action, we designed the treatments involving gemcitabine either alone or in combination with ZD1839. We found that ERK activation and AKT inactivation contributed to gemcitabine-induced apoptosis in NSCLC. When ZD1839 and gemcitabine were given in combination or sequence, gemctibine followed by ZD1839 induced the greatest induction of apoptosis. However, the sequential treatment ZD1839 followed by gemcitabine caused an antagonistic interaction. Our findings suggest that the interaction of ZD1839 and gemcitabine is highly schedule dependent. |
