131I-17-AAG对荷H460人非小细胞肺癌裸鼠的抗癌效应

目的 观察131I标记17-丙烯胺基-17-去甲氧基格尔德霉素(17-KAG)对荷H460人非小细胞肺癌裸鼠移植瘤的抑癌效应.方法 过氧化氢法制备131I-17AAG.建立荷H460人非小细胞肺癌BALB/c裸鼠模型,28只荷瘤裸鼠按随机数字表法分为7组(n=4),瘤内和尾静脉注药各3组,剂量依次为5.5 MBq×2(间隔8 d)、11.0 MSq和5.5 MBq及空白对照组.另设Na131I瘤内给药对照组.8组分别于注药后2,6,24 h及2,3,7,10,16 d各取2只鼠行γ显像.观察肿瘤生长情况,16 d后处死全部小鼠,计算抑瘤率,并做光学显微镜、电镜及免疫组织化学检测.计量数据以x±s表示,采用SPSS 13.0软件进行统计分析.结果 SPECT显像证实131I-17-AAG靶向定位好,能较长时间聚集在瘤体内;各治疗组存在不同程度抑瘤效应,以瘤内间隔给药(5.5 MBq×2)组疗效最好,抑瘤率高达(86.77±4.57)%,尾静脉给药5.5 MBq×2组和11.0 MBq组间差异无统计学意义(q=1.67,P>0.05),余各组间抑瘤率差异均有统计学意义(q=3.16～24.34,P均<0.05);形态学显示抑瘤效应越好,瘤组织破坏越明显;免疫组织化学显示瘤内及尾静脉注药组热休克蛋白90(HSP90)a阳性率分别为(26.01±3.71)%、(61.57±5.98)%]均较空白对照组(84.13±5.71)%]下降(t值分别为20.91和6.68,P均<0.05).结论 131I-17-AAG能有效抑制裸鼠非小细胞肺癌的生长,以瘤内注药及间隔给药抑癌效应最佳.

Anti-tumor effect of 131I labeled 17-allylamina-17-demethaxygeldunamyda on human non-small cell lung cancer in xenograft-bearing nude mice

Objective 17-allylamino-17-demethoxygeldanamycin (17-AAG) has been developed as a novel heat shock protein 90 (HSP90) inhibitor being used in clinical trials. HSP90 is known as a molecular target for tumor therapy. The goal of this study was to investigate the inhibitive effects of 131Ⅰ labeled 17-AAG on human non-small cell lung cancer in xenograft-bearing nude mice. Methods 17-AAG was laDeled with 131Ⅰ. Twenty-eight BALB/c nude mice bearing H460 human non-small cell lung carcinoma tumor xenograft were randomly divided into seven groups, one control group and six treatment groups according to the route of administration (via tail vein injection or intratumoral injection) and the doses of injected radioactivity (5.5 MBq × 2 with 8 d interval, 11.0 MBq and 5.5 MBq). Two additional mice were treated with intratumoral injection of Na131Ⅰsolution that was served as scintigraphic imaging controls. In each group two mice underwent scintigraphy at2 h, 6 h, 24 h, 2 d, 3 d, 7 d, 10 d and 16 d. After 16 d the tumor inhibition rate was calculated. Then all of the mice were sacrificed and the tumor tissues were obtained for histological examination and immunohistochemical assay. Results Persistent accumulation of 131Ⅰ-17-AAG in the tumors was seen on scintigraphic images. Tumor inhibiting effect was demonstrated in all treatment groups with varying degrees. The highest tumor inhibition rate (86.77±4.57) % was shown in the group with interval intratumoral injection (5.5 MBq×2). There was no significant difference of tumor inhibition rates between 5.5 MBq×2 group (via tail vein injection) and 11.0 MBq group(via tail vein injection, q =1.67, P>0.05). While among the other treatment groups, there was significant difference in tumor inhibition rates(q =3.16-24.34, all P<0.05). The morphologic changes paralleled with the tumor inhibition rates. Tumor cell HSP90α antigen expression rate was significantly lower in the intratumoral injection groups (26.01±3.71)% and in tail vein injection groups (61.51±5.98)% than that of control group (84.13±5.71, t = 20.91 and 6.68, all P < 0.05). Conclusions 131Ⅰ-17-AAG may effectively inhibit the tumor growth and expression of HSP90α antigen expression in non-small cell lung cancer bearing nude mice. The more prominent anti-tumor effect may be obtained by the administration of interval intratumoral injection.