开环及闭环羟基喜树碱对口腔鳞癌细胞株抗癌作用的研究  

Antitumor Effects of Ring-closed and Ring-opened Hydroxycamptothecin on Oral Squamous Carcinoma Cell Line Tca8113

作　　者：王安训[1] 李苏[2] 丁学强[1] 陈宇[1] 陈丹[1] 

机构地区：[1]中山大学附属第一医院口腔科,广东广州510080 [2]中山大学附属肿瘤医院华南肿瘤学国家重点实验室,广东广州510060

出　　处：《癌症》2005年第8期970-974,共5页Chinese Journal of Cancer

基　　金：广东省卫生厅基金(No.A2002189);广东省科技计划项目(No.2004B30901002)~~

摘　　要：背景与目的:羟基喜树碱(hydroxycamptothecin,HCPT)的抗癌活性与其内酯环(包括闭环和开环)密切相关,但关于闭环HCPT和开环HCPT的抗癌活性仍有争议,研究已显示开环HCPT对口腔鳞癌具有明显的体内外抑制作用,本文比较开环及闭环HCPT对口腔鳞癌细胞株Tca8113的体内外抗瘤作用及其作用机理。方法:采用开环及闭环HCPT处理Tca8113细胞及其裸鼠移植瘤,MTT法及流式细胞仪(FCM)检测HCPT对Tca8113细胞的细胞毒作用及对细胞周期的影响;观察经HCPT处理后Tca8113细胞移植瘤的生长状态,计算肿瘤倍增时间和抑瘤率;高效液相色谱仪检测裸鼠血浆及移植瘤中HCPT的浓度,计算药代动力学参数。结果:开环及闭环HCPT对Tca8113细胞具有相同的强杀伤作用,FCM检测显示小于1μmol/LHCPT可将细胞阻滞在S期和G2/M期,100μmol/LHCPT则诱导细胞凋亡。与对照组比较,HCPT组移植瘤生长减慢,倍增时间延长,肿瘤抑制率分别为69.6%(3mg/kg开环HCPT)、65.0%(3mg/kg闭环HCPT)和74.1%(10mg/kg开环HCPT)。腹腔注射10mg/kgHCPT后裸鼠血浆曲线下面积分别为2.66μg·h·ml-1(闭环HCPT)和0.42μg·h·ml-1(开环HCPT),肿瘤组织中可检测到HCPT。HCPT3mg/kg组未见明显的毒副作用,开环HCPT10mg/kg组可见明显的胃肠道反应,闭环HCPT10mg/kg组所有裸鼠死亡。结论:开环及闭环HCPT均对口腔鳞癌细胞具有强的体内外细胞毒作用,其机理与阻断细胞于S期和G2/M期以及诱导细胞凋亡有关,但闭环HCPT毒性较开环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 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 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 （ 〈 1 μmol/L） arrested cell cycle of Tca8113 cells at S phase and G2/M phase； high concentration of HCPT （100 μmol/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 μg.h.ml^-1 for C-HCPT （10 mg/kg）and 0.42 μg.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. CONCLUSIONS： Both C-HCPT and O-HCPT have strong in vitro and in vivo cytotoxic effects on Tca

关 键 词：羟基喜树碱/药理学 口腔肿瘤 TEA8113细胞 凋亡 移植瘤 小鼠 

分 类 号：R739.8[医药卫生—肿瘤]