Wang An-Xun, Li Su, Ding Xue-Qiang, Chen Yu, Chen Dan
Department of Stomatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
Ai Zheng. 2005 Aug;24(8):970-4.
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.
Tca8113 cells and its xenografts in BALB/C nude mice were treated with C-HCPT 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 observedû 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.
C-HCPT and O-HCPT showed similar cytotoxicity effects on Tca8113 cells in vitro. Low concentration of HCPT (< 1 micromol/L) arrested cell cycle of Tca8113 cells at S phase and G(2)/M phase; high concentration of HCPT (100 micromol/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% (3 mg/kg of O-HCPT), 65.0% (3 mg/kg of C-HCPT), and 74.1% (10 mg/kg of O-HCPT), respectively. The plasma AUC was 2.66 microg . h . ml(-1) for C-HCPT (10 mg/kg) and 0.42 microg . h . ml(-1) for O-HCPT (10 mg/kg). HCPT could be detected in tumor tissue. No obvious toxicity was observed in 3 mg/kg of HCPT group; obvious gastrointestinal reaction was observed in 10 mg/kg of O-HCPT group; all nude mice in 10 mg/kg of C-HCPT group died 2 days after treatment.
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.
羟基喜树碱（HCPT）的抗肿瘤作用与其内酯形式（包括环合形式和开环形式）密切相关，但环合型HCPT（C-HCPT）和开环型HCPT（O-HCPT）的抗肿瘤作用仍存在争议。研究表明，O-HCPT对口腔鳞状细胞癌具有明显的体内外抗肿瘤作用。本研究旨在比较C-HCPT和O-HCPT对口腔鳞状癌细胞系Tca8113的抗肿瘤作用，并探讨其作用机制。
用C-HCPT和O-HCPT处理Tca8113细胞及其在BALB/C裸鼠体内的异种移植瘤。采用MTT法检测HCPT的细胞毒性。通过流式细胞术检测细胞周期。观察Tca8113细胞异种移植瘤的生长状态，计算肿瘤倍增时间和抑制率。采用高效液相色谱法（HPLC）定量血浆和肿瘤组织中总HCPT的浓度；估算药代动力学参数。
C-HCPT和O-HCPT对体外培养的Tca8113细胞显示出相似的细胞毒性作用。低浓度HCPT（<1 μmol/L）使Tca8113细胞的细胞周期阻滞于S期和G2/M期；高浓度HCPT（100 μmol/L）明显诱导Tca8113细胞凋亡。与对照组相比，HCPT处理组的异种移植瘤生长缓慢，肿瘤倍增时间延长。肿瘤抑制率分别为69.6%（3 mg/kg O-HCPT）、65.0%（3 mg/kg C-HCPT）和74.1%（10 mg/kg O-HCPT）。C-HCPT（10 mg/kg）的血浆AUC为2.66 μg·h·ml-1，O-HCPT（10 mg/kg）的血浆AUC为0.42 μg·h·ml-1。在肿瘤组织中可检测到HCPT。3 mg/kg HCPT组未观察到明显毒性；10 mg/kg O-HCPT组观察到明显的胃肠道反应；10 mg/kg C-HCPT组的所有裸鼠在治疗后2天死亡。
C-HCPT和O-HCPT对Tca8113细胞均具有较强的体内外细胞毒性作用，这与细胞周期阻滞和诱导细胞凋亡有关。C-HCPT的细胞毒性比O-HCPT更严重。
