核因子-κB抑制剂增强^131I治疗甲状腺癌疗效的裸鼠实验研究

Enhancement of ^131I therapeutic efficacy on differentiated thyroid cancer by nuclear factor-KB inhibitor in nude mice

目的通过小鼠活体研究，探讨核因子-κB抑制剂Bay11-7082在^131I治疗DTC中的协同作用。方法通过裸鼠腹腔注射37MBq ^131I，制备清除甲状腺裸鼠模型。将72只种植KTC-1癌细胞的清除甲状腺裸鼠随机分为4组：单独用^131I组、单独用Bay11-7082组、联合用药组和对照组。给药方法为：^131I剂量37MBq，于种植癌细胞第7周第1天腹腔注射；Bay11-7082剂量按体质量10mg／ks，于第7周第1、2和3天腹腔注射；联合用药组两药合用，剂量同上；对照组腹腔注射相同体积的生理盐水。成瘤后每周第7天测量癌结节大小，绘制癌结节体积变化曲线。裸鼠清除甲状腺前行^99Tc^mO4^-显像，^131I清除甲状腺后和^131I治疗种植瘤后3d行全身显像（单独用Bay11-7082组未行治疗后显像）。第7周第7天从每组中取6只裸鼠处死，对癌结节进行凋亡染色，计算凋亡指数（染色阳性细胞数／总细胞数×100％）。用单因素方差分析和q检验进行数据比较。结果裸鼠^99Tc^mO4^-显像可见甲状腺和胃显影；清除甲状腺时腹腔注射^131I后显像可见甲状腺^131I浓聚明显；^131I治疗后荷裸鼠全身显像可见癌结节^131I浓聚。从第8周末开始，3种治疗方案所致的癌结节体积改变差异有统计学意义（F=11．91—246．56，均P〈0．01），联合用药组癌结节体积明显小于单一用药组（q=3．36—14．99，均P〈0．01）。对照组、^131I治疗组、Bay11-7082治疗组和联合用药组的凋亡指数分别为（0．28±0．15）％、（5．49±0．69）％、（6．82±0．72）％和（16．21±1．57）％，差异有统计学意义（F=304．40，P〈0．01）；其中联合用药组明显高于单独用药组（q=15．33和13．33，均P〈0．01）。结论裸鼠体内实验显示，通过Bay11-7082对核因子-κB通路的抑制，可以增强^131I治疗甲状腺癌的疗效，产生协同效应。

Objective To study whether Bay 11-7082, a nuclear factor-kappa B （NF-KB） inhibi- tor,could enhance the treatment efficacy of 131I on DTC in nude mice. Methods Total thyroid ablation nude mice models were prepared by intraperitoneal injection of 37 MBq 1311. The xenografted mice were divided into 4 groups （18/group） ： 131I group, Bay 11-7082 group, combination of ^131I and Bay 11-7082 group and control group. Drug dosages were given as： intraperitoneal injection of 37 MBq 131I on day 1 in the 7th week in the ^131I group; intraperitoneal injection of 10 mg/kg Bay 11-7082 on day 1, 2 and 3 in the 7^th week in the Bay 11-7082 group; intraperitoneal injection of both 131I and Bay 11-7082 as above-mentioned in the combined treatment group; injection of saline in the control group. The xenografted tumor volume curves were drawn every 7 days. Perteehnetate imaging was performed before thyroid ablation. Post-ablative and post-therapeutic 131I whole body imaging was conducted. On day 7 in the 7^th week, 6 mice in each group were sacrificed and apoptotie staining was performed on excised xenograft tumors. Apoptosis index was determined as positive cells over total cells × 100%. One-way analysis of variance and q test were performed for statistical analysis. Results Thyroid and stomach could be visualized on perteehnetate imaging before thyroid ablation. Post-ablative 131I imaging showed increased uptake by the thyroid gland. Post-therapeutic 131I imaging showed increased uptake by the malignant tumor lesions in both the 131I and combined groups. Tumor volume curves showed significant differences in volume changes among different methods of therapy from the end of the 8th week （F = 11.91 -246.56, all P 〈0.01 ）. Combined treatment was more effective than single-therapies （ q = 3.36 - 14.99, all P 〈 0.01 ）. Apoptosis indices for the control group, 131I group, Bay 11-7082 group and combined group were （0.28 ± 0.15 ） %, （ 5.49 ± 0.69） %, （ 6.82 ± 0.72） % and （ 16.21 ± 1.57 ） %, respectively （ F = 304.40, P 〈 0.01 ）. Apoptosis index in the combined group was significantly higher than those in each single therapy group （q = 15.33 and 13.33, both P 〈0.01 ）. Conclusion NF-κB inhibition by Bay 11-7082 could effectively enhance the treatment efficacy of 131I on DTC.