维甲酸联合曲古抑素诱导及治疗荷人甲状腺滤泡状癌裸鼠的实验研究

Effect of all-trans retinoic acid combined with trichostatin A on the nude mice bearing human follicular thyroid carcinoma

目的探讨全反式维甲酸（ATRA）和曲古抑素（TSA）对人甲状腺滤泡状癌细胞株（FTC-133）和荷人甲状腺滤泡状癌裸鼠（NMB—hFTC）肿瘤模型摄碘能力的影响。方法不同量ATRA、TSA诱导VFC-133细胞：ARTA 1．0×10^-6mo／L（A低组）、1．0×10^-4mol／L（A高组）、TSA1．65×10^-7mol／L（T组）、A低＋T组、A高＋T组和无水乙醇（对照组），96h后行HE染色，测定FTC-133细胞摄碘率；制备NMB—hFTC，成瘤后分组：ATRA组（2mg／kg灌胃）、TSA组（10mg／kg腹腔注射）、联合组（ATRA＋TSA，用量同前）、对照组（生理盐水灌胃＋腹腔注射，均为10ml／kg），剂量均按鼠体质量给予。给药22d后，腹腔注射37MBq ^131I，分别于注射后4，6，12和24h行γ显像，测定体内生物分布；显像后取肿瘤组织行HE染色观察细胞形态。实验结果采用SPSS13．0软件进行单因素方差分析。结果FTC-133细胞摄碘率A低＋T组、A高＋T组分别为（23885±616．0）和（13849±728．2）计数·min^-1·10^-6细胞，其他各组在（985±84．2）～（17600±782．7）计数·min^-1·10^-6细胞范围内，各组间比较差异有统计学意义（F=600．879，P〈0．001）。^131I注射后6，12和24h联合组裸鼠种植瘤％ID／g分别为6．17±0．46，9．34±0．61，11．19±0．98，其余各组保持在（1．97±0．34）～（5．14±0．65）之间；肿瘤质量各组间比较差异有统计学意义（F=3．723，P〈0．05）。结论ATRA联合TSA，可增强FTC-133细胞和NMB—hFTC病灶的分化、摄碘能力，达到增强^131I杀死甲状腺癌病灶的协同作用。

Objective To study the changes of iodine uptake of the follicular thyroid carcinoma cell line （FTC-133） and nude mice bearing human follicular thyroid carcinoma after the induction with alltrans retinoic acid （ATRA） , trichostatin A （TSA） or ATRA combined with TSA. Methods After the induction with ATRA, TSA, or ATRA combined with TSA in different concentrations for 96 h, the iodine uptake of FTC-133 ceils was observed. The concentrations for different groups were as follows： ATRA 1.0 × 10^-6 mol/L（Alow group）, ATRA 1.0 ×10^-4 mol/L（Ahigh group）, TSA 1.65 ×10^-7 mol/L（T group）, Alow ＋ T group, Ahigh ＋ T group and ethanol （control group）. Cell quantities and morphology were observed by HE staining. FTC-133 cells were subcutaneously injected into nude mice. Twelve nude mice were randomly divided into 4 groups after tumor formation： ATRA group （2 mg/kg, intragastric administration）, TSA group （10 mg/kg, intraperitoneal injection）, combined therapy group （ATRA ＋ TSA, the same doses as above） and saline control group （10 ml/kg, intragastric and intraperitoneal administration, respectively）. Drugs were administered to the tumor-bearing mice according to the mouse body mass daily. At the 22nd day, the tumor-bearing mice were injected with 37 MBq ^131I intraperitoneally. The biodistribution of ^131I and gamma imaging were performed at 4, 6, 12 and 24 h after the injection respectively. Histopathological examinations of the tumor samples were taken after imaging completion. The results were analyzed by analysis of variance （ANOVA） with SPSS 13.0. Results The cellular iodine uptake were （23 885± 616.0） and （13 849 ±728.2） counts · min^-1 · 10^-6 cells in the Alow ＋ T group and Ahigh ＋ T group respectively, and the data were （985 ± 84.2） - （ 17 600 ± 782.7） counts · min ^-1 · 10 ^-6 in the other groups （ F = 600. 879, P 〈 0. 001 ）. The % ID/g of tumor at 6 h was 6.17± 0.46 in the combined group and it increased to 9.34 ± 0. 61 at 12 h and 11.19 ±0.98 at 24 h. The % ID/g of tumor in the other groups were from （ 1.97±0.34） to （ 5.14 ± 0.65 ）. The tumor qualities of the 4 groups were significantly different （ F = 3. 723, P 〈 0.05 ）. Conclusion The iodine uptake of the tumor could be enhanced in the tumor-bearing mice administered with ATRA combined with TSA, a potential way for treating follicular thyroid carcinoma.