Enhancement of somatostatin-receptor-targeted (177)Lu-[DOTA(0)-Tyr(3)]-octreotide therapy by gemcitabine pretreatment-mediated receptor uptake, up-regulation and cell cycle modulation.
Enhancement of somatostatin-receptor-targeted (177)Lu-[DOTA(0)-Tyr(3)]-octreotide therapy by gemcitabine pretreatment-mediated receptor uptake, up-regulation and cell cycle modulation.
复制标题
通过吉西他滨预处理介导的受体摄取、上调和细胞周期调节增强生长抑素受体靶向 (177)Lu-[DOTA(0)-Tyr(3)]-奥曲肽治疗。
DOI：
10.1016/j.nucmedbio.2008.05.003
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发表时间：
2008
影响因子：
3.1
通讯作者：
Norenberg,JeffreyP
中科院分区：
文献类型：
--
作者：
Nayak,TapanK;Atcher,RobertW;Prossnitz,EricR;Norenberg,JeffreyP
简介针对生长抑素受体 (sstr) 治疗的患者的临床研究 [DOTAdeg. C，-Tyr{sup 3}]-奥曲肽 (DOTATOC)，用 {sup 177}Lu 和 {sup 9}deg 标记。 C、Y 的总体响应率在 9-33% 范围内。本研究评估了吉西他滨联合治疗的潜力，以改善临床结果。 方法将人胰腺腺癌 Capan-2、大鼠胰腺癌 AR42J 和人小细胞肺癌 NCI-H69 细胞分别用 1 {μ}g/ml 吉西他滨处理 4 天，然后单独更换培养基另外 4 天。在如上所述的总共 8 天治疗后，用 {sup 177}Lu-DOTATOC 进行细胞周期和直接受体摄取研究。进行细胞活力和凋亡实验以研究吉西他滨预处理和{sup 177}Lu-DOTATOC放射性核素治疗的效果。使用非靶向受体的 {sup 177}Lu-DOTA 和 DOTATOC 进行平行对照研究。结果用吉西他滨处理 4 天的细胞显示出 sstr 表达的下调，如通过 {sup 177}Lu-DOTATOC 摄取所确定的。然而，在没有吉西他滨的情况下额外生长4天后，{sup 177}Lu-DOTATOC的摄取比未处理的对照细胞高1.5-3倍。在吉西他滨预处理的 Capan-2 细胞中，84% 的细胞群处于细胞周期的 G{sub 2}M 期。由于 sstr 上调和细胞周期调节，在细胞活力和细胞凋亡测定中观察到吉西他滨预处理的协同作用。 {sup 177}Lu-DOTATOC 导致吉西他滨预处理的 Capan-2 细胞的细胞凋亡比未处理的细胞高出两到三倍。结论吉西他滨预处理上调 sstr 表达并通过细胞周期调节充当放射增敏剂。吉西他滨和 sstr 靶向放射性药物的合理组合代表了一种有前途的放化疗治疗工具，具有改善临床结果的巨大潜力，因此值得进一步研究。
IntroductionClinical studies of patients treated with somatostatin-receptor (sstr)-targeted [DOTAdeg. C, -Tyr{sup 3}]-octreotide (DOTATOC) labeled with {sup 177}Lu and {sup 9}deg. C, Y have shown overall response rates in the range of 9-33%. This study evaluates the potential for combination therapy with gemcitabine in an effort to improve clinical outcomes.MethodsHuman pancreatic adenocarcinoma Capan-2, rat pancreatic cancer AR42J and human small cell lung cancer NCI-H69 cells were each treated with 1 {mu}g/ml gemcitabine for 4 days followed by replacement of the medium alone for four additional days. Cell cycle and direct receptor-uptake studies were performed with {sup 177}Lu-DOTATOC after the total 8-day treatment as described. Cell viability and apoptosis experiments were performed to study the effects of gemcitabine pretreatment and {sup 177}Lu-DOTATOC radionuclide therapy. Parallel control studies were performed with receptor-non-targeted {sup 177}Lu-DOTA and DOTATOC.ResultsCells treated with gemcitabine for 4 days showed a down-regulation of sstr expression as determined by {sup 177}Lu-DOTATOC uptake. However, after 4 days of additional growth in absence of gemcitabine, the uptake of {sup 177}Lu-DOTATOC was 1.5-3 times greater than that of the untreated control cells. In gemcitabine-pretreated Capan-2 cells, 84% of the cell population was in the G{sub 2}M phase of the cell cycle. Due to sstr up-regulation and cell cycle modulations, synergistic effects of gemcitabine pretreatment were observed in cell viability and apoptosis assays. {sup 177}Lu-DOTATOC resulted in two to three times greater apoptosis in gemcitabine-pretreated Capan-2 cells compared to the untreated cells.ConclusionGemcitabine pretreatment up-regulates sstr expression and acts as a radiosensitizer through cell cycle modulation. The rational combination of gemcitabine and sstr-targeted radiopharmaceuticals represents a promising chemoradiation therapeutic tool with great potential to improve clinical outcomes and, thus, merits further study.