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

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,检测其中血管内皮生长因子(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mTOR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。

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

ObjectiveTo explore the in vitro synergistic anti-tumor efficacy of mammalian target of rampamycin (mTOR) 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 mTOR inhibitor. ResultsMter several cycles of radiation induction (3 Gy ),the radio-resistant ceils 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. ConclusionRAD001 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 may inhibit synergistically the growth of radio-resistant tumors.