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首页> 外文期刊>Molecular urology >Antitumor effect of bcl-2 antisense phosphorothioate oligodeoxynucleotides on human renal-cell carcinoma cells in vitro and in mice.
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Antitumor effect of bcl-2 antisense phosphorothioate oligodeoxynucleotides on human renal-cell carcinoma cells in vitro and in mice.

机译：bcl-2反义硫代磷酸酯寡脱氧核苷酸在体外和小鼠中对人肾细胞癌细胞的抗肿瘤作用。

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BACKGROUND AND PURPOSE: Programmed cell death is a genetically regulated pathway that is altered in many cancers. This process is, in part, regulated by the bcl-2 oncogene. Antisense oligodeoxynucleotides (ODNs) targeted to specific oncogenes have been used with some therapeutic success in animal models of leukemia and melanoma cells and human Hodgkin's lymphoma. We evaluated the effects of antisense ODNs targeted to the bcl-2 oncogene on the proliferation of human renal-cell carcinoma (RCC) cells in vitro and on the growth of human RCC xenografts in BALBc nude (nuu) mice. MATERIALS AND METHODS: Expression bcl-2 mRNA in five RCC cell lines (ACHN, Caki-1, RCZ, RCW, and OS-RC-2) was analyzed by reverse transcriptase-polymerase chain reaction. The effects of phosphorothioated ODNs containing human bcl-2 sense and bcl-2 antisense sequences that were transfected with Lipofectin on the proliferation and viability of cultures of established human RCC cell lines were determined by MTS assay. The expression of Bcl-2 protein in ACHN tumor cells following antisense bcl-2 (AS2) ODN treatment was evaluated by Western blot analysis, and the extent of apoptosis in these cells was determined by fluorescence-activated cell sorter (FACS) analysis. The antitumor activity in ACHN xenografts in nuu mice was monitored by measuring differences in tumor weight in treated and control mice. RESULTS: Expression of bcl-2 mRNA was detected in all five RCC lines. Treatment with antisense bcl-2 ODNs inhibited the growth of all tested RCC cells and decreased Bcl-2 protein expression in ACHN cells. The AS2 antisense ODN complementary to the coding region of bcl-2 mRNA showed a superior antiproliferative effect compared with AS1 ODN complementary to the translation initiation region. Inhibition by antisense bcl-2 ODNs of ACHN cells was dose dependent. The FACS analysis revealed that growth inhibition was associated with the induction of programmed cell death. In vivo, AS2 ODN antitumor activity was noted in locally injected groups. CONCLUSIONS: Treatment of human RCC with antisense ODNs targeted to bcl-2 inhibits growth and is associated with the induction of programmed cell death. These results suggest therapeutic use of antisense bcl2 in the treatment of RCC.
机译：背景与目的：程序性细胞死亡是一种遗传调控的途径，在许多癌症中都有所改变。此过程部分受bcl-2癌基因调控。在白血病和黑色素瘤细胞以及人类霍奇金淋巴瘤的动物模型中，已将针对特定致癌基因的反义寡脱氧核苷酸（ODN）用于治疗，取得了一定的成功。我们评估了针对bcl-2癌基因的反义ODN对BALBc裸鼠（nu / nu）小鼠体外人肾细胞癌（RCC）细胞增殖和人RCC异种移植物生长的影响。材料与方法：通过逆转录聚合酶链反应分析了5种RCC细胞系（ACHN，Caki-1，RCZ，RCW和OS-RC-2）中bcl-2 mRNA的表达。通过MTS测定确定了用脂质体转染的含有人bcl-2有义和bcl-2反义序列的硫代磷酸化ODN对已建立的人RCC细胞系培养物的增殖和生存力的影响。通过蛋白质印迹分析评估反义bcl-2（AS2）ODN处理后ACHN肿瘤细胞中Bcl-2蛋白的表达，并通过荧光激活细胞分选仪（FACS）分析确定这些细胞中的凋亡程度。 nu / nu小鼠中ACHN异种移植物中的抗肿瘤活性通过测量治疗和对照小鼠的肿瘤重量差异来监测。结果：在所有5个RCC细胞系中均检测到bcl-2 mRNA的表达。用反义bcl-2 ODNs处理可抑制所有测试的RCC细胞的生长，并降低ACHN细胞中Bcl-2蛋白的表达。与bcl-2 mRNA编码区互补的AS2反义ODN与与翻译起始区互补的AS1 ODN相比，具有优越的抗增殖作用。反义bcl-2 ODN对ACHN细胞的抑制作用是剂量依赖性的。 FACS分析表明，生长抑制与程序性细胞死亡的诱导有关。在体内，在局部注射组中发现了AS2 ODN抗肿瘤活性。结论：以bcl-2为靶点的反义ODNs治疗人RCC可抑制其生长，并与程序性细胞死亡的诱导有关。这些结果表明反义bcl2在RCC的治疗中的治疗用途。

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