依维莫司逆转放射耐受发挥与5-氟尿嘧啶的协同抗肿瘤作用  

RAD001 reverses radio-resistance and exerts synergistic tumor inhibition with 5-fluorouracil

作　　者：忻莹[1] 丛伟[1] 周宁[1] 洪德飞[1] 蔡秀军[1] 

机构地区：[1]浙江大学医学院附属邵逸夫医院普外科,浙江大学微创外科研究所,杭州310016

出　　处：《中华医学杂志》2011年第36期2564-2567,共4页National Medical Journal of China

基　　金：浙江省教育厅科研项目（Y200803714）

摘　　要：目的观察在胰腺癌和结肠癌的体外实验中，依维莫司（RAD001）发挥血管新生抑制作用的同时对5-氟尿嘧啶（5-Fu）是否有增敏效果。方法在体外细胞培养人胰腺癌AsPC、人结肠癌细胞HT29，并经大剂量放射线诱导建立放射耐受株AsPCres和HT29res，检测其中血管内皮牛长因子（VEGF）和胸腺嘧啶磷酸化酶（TP）的表达情况；然后分别给予单独5-Fu化疗，5-Fu和roTOR抑制剂RAD001的联合化疗方案，观察肿瘤细胞的增殖情况。结果通过多个周期的大剂量放射诱导（3Gy），可建立人胰腺癌放射耐受株AsPCres和人结肠癌放射耐受株HT29res；AsPCres和HT29res的VEGF的表达高于亲株，分别为（1215±67）pg／ml和（689±25）pg／ml，分别与各自亲株相比，差异有统计学意义，P〈0．01；放射耐受株的TP表达较亲株也有所上调；5-FU和mTOR抑制剂RAD001的联合方案可协同抑制肿瘤细胞的增殖，在HT29亲株和放射耐受株中，联合方案组（RAD001＋5-FU）的细胞存活率分别为58．4％和75．9％，而单独5-Fu给药组的细胞存活率分别为73．9％和87．4％。结论mTOR抑制剂和5-FU的联合化疗方案可抑制放射耐受株肿瘤细胞的生长。这可能是RAD001抑制了肿瘤内放射诱导的VEGF表达；放射诱导肿瘤细胞上调TP的表达，使5-Fu增敏。Objective To explore the in vitro synergistic anti-tumor efficacy of mammalian target of rampamycin （roTOR） inhibitor （ RADO01 ） and 5-fluorouracil （5-FU） for radio-resistant tumors. Methods Radio-resistant cells of human pancreatic cancer cell and human colon cancer cell were established. The expression profiles of VEGF （vascular endothelial growth factor） and TP （thymidine phosphorylase） were compared between parental and radio-resistant tumor cells. The tumor proliferation was analyzed after 5-FU alone or in combination with a roTOR inhibitor. Results After several cycles of radiation induction （3 Gy）, the radio-resistant cells of human pancreatic cancer（AsPCres） and colon cancer（HT29res） were established. There was a higher expression of VEGF in radio-resistant tumor cells than their parental cells. They were 1215 -＋67 pg/ml in AsPCres and 689 -＋25 pg/ml in HT29res respectively （P 〈0. 01）. The up-regulation of TP was observed in both AsPC-res and HT29-res. The combined therapy of 5-FU plus a mTOR inhibitor might exert synergistic tumor inhibition, Conclusion RAD001 decreases the radiation-induced expression of VEGF in tumor. And the post-radiation up-regulation of TP promotes the efficacy of 5-FU. The combined therapy of RAD001 and 5-FU mav inhibit svnergisticallv the growth of radio-reslstant tumors.

关 键 词：依维莫司 5-氟尿嘧啶 抗肿瘤药 

分 类 号：R735.35[医药卫生—肿瘤] R735.9[医药卫生—临床医学]