Antitumor Effects of Ring-closed and Ring-opened Hydroxycamptothecin on Oral Squamous Carcinoma Cell Line Tca8113
王安訓(An-Xun Wang)；李蘇(Su Li)；丁學強(Xue-Qiang Ding)；陳宇(Yu Chen)；陳丹(Dan Chen)
羥基喜樹鹼／藥理學 ； 口腔腫瘤 ； Tca8113細胞 ； 凋亡 ； 移植瘤 ； 小鼠 ； Hydroxycamptothecin/pharmacology ； Oral neoplasms ； Tca8113 cells ； Apoptosis ； Xenografts ； Mouse
|Volume or Term/Year and Month of Publication||
24卷8期（2005 / 08 / 05）
970 - 974
背景與目的：羥基喜樹鹼(hydroxycamptothecin，HCPT)的抗癌活性與其內酯環（包括閉環和開環）密切相關，但關於閉環HCPT和開環HCPT的抗癌活性仍有爭議，研究已顯示開環HCPT對口腔鱗癌具有明顯的體內外抑制作用，本文比較開環及閉環HCPT對口腔鱗癌細胞株Tca8113的體內外抗瘤作用及其作用機理。方法：採用開環及閉環HCPT處理Tca8113細胞及其裸鼠移植瘤，MTT法及流式細胞儀(FCM)檢測HCPT對Tca8113細胞的細胞毒作用及對細胞週期的影響；觀察經HCPT處理後Tca8113細胞移植瘤的生長狀態，計算腫瘤倍增時間和抑瘤率；高效液相色譜儀檢測裸鼠血漿及移植瘤中HCPT的濃度，計算藥代動力學參數。結果：開環及閉環HCPT對Tca8113細胞具有相同的強殺傷作用，FCM檢測顯示小於1μmol/L HCPT可將細胞阻滯在S期和G2/M期，100μmol/L HCPT則誘導細胞凋亡。與對照組比較，HCPT組移植瘤生長減慢，倍增時間延長，腫瘤抑制率分別為69.6%（3mg/kg開環HCPT）、65.0%（3mg/kg閉環HCPT）和74.1%（10mg/kg開環HCPT）。腹腔注射10mg/kg HCPT後裸鼠血漿曲線下面積分別為2.66μg•h•ml^(-1)，（閉環HCPT）和0.42μg•h•ml^(-1)（開環HCPT），腫瘤組織中可檢測到HCPT。HCPT 3mg/kg組未見明顯的毒副作用，開環HCPT 10mg/kg組可見明顯的胃腸道反應，閉環HCPT 10mg/kg組所有裸鼠死亡。結論：開環及閉環HCPT均對口腔鱗癌細胞具有強的體內外細胞毒作用，其機理與阻斷細胞於S期和G2/M期以及誘導細胞凋亡有關，但閉環HCPT毒性較開環HCPT毒性大。
Background & Objective: The antitumor effect of hydroxycamptothecin (HCPT) closely relates with its lactone form (including ring-closed form and ring-opened form), but the antitumor effects of ring- closed HCPT (C-HCPT) and ring-opened HCPT (O-HCPT) remain controversial. Researches have showed that O-HCPT has obvious in vitro and in vivo antitumor effects on oral squamous cell carcinoma. This study was to compare the antitumor effects of C-HCPT and O-HCPT on oral squamous carcinoma cell line Tca8113, and explore the mechanisms. Methods: Tca8113 cells and its xenografts in BALB/C nude mice were treated with CHCPT and O-HCPT. The cytotoxicity of HCPT was measured by MTT assay. Cell cycle was detected by flow cytometry. The growth state of Tca8113 cells xenografts was observed; the tumor doubling time and inhibition rate were calculated. The concentration of total HCPT in plasma and tumor tissue was quantitated by high-performance liquid chromatography (HPLC); the pharmacokinetic parameters were estimated. Results: C-HCPT and O-HCPT showed similar cytotoxicity effects on Tca8113 cells in vitro. Low concentration of HCPT (＜1μmol/L) arrested cell cycle of Tca8113 cells at S phase and G2/M phase; high concentration of HCPT (100μmol/L) obviously induced apoptosis of Tca8113 cells. Compared with control group, the xenografts of HCPT-treated group grew slowly, and the tumor doubling time was prolonged. The tumor inhibition rates were 69.6% (3mg/kg of O-HCPT), 65.0% (3mg/kg of C-HCPT), and 74.1% (10mg/kg of O-HCPT), respectively. The plasma AUC was 2.66μg•h•ml^(-1) for O-HCPT (10mg/kg) and 0.42 μg•h•ml^(-1) for O-HCPT (10mg/kg). HCPT could be detected in tumor tissue. No obvious toxicity was observed in 3mg/kg of HCPT group; obvious gastrointestinal reaction was observed in 10mg/kg of O-HCPT group; all nude mice in 10mg/kg of C-HCPT group died 2 days after treatment. Conclusions: Both C-HCPT and O-HCPT have strong in vitro and in vivo cytotoxic effects on Tca8113 cells, which relate to cell cycle arrest and cell apoptosis inducement. Cytotoxicity of C-HCPT is more severe than that of O-HCPT.