Inhibition of Burkitt's lymphoma cells growth in SCID mice by a PNA specific for a regulatory sequence of the translocated c-myc
Inhibition of Burkitt's lymphoma cells growth in SCID mice by a PNA specific for a regulatory sequence of the translocated c-myc
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DOI：
10.1038/sj.cgt.7701002
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发表时间：
2007-02-01
影响因子：
6.4
通讯作者：
Ferrarini, M.
中科院分区：
文献类型：
--
作者：
Boffa, L. C.;Cutrona, G.;Ferrarini, M.
在伯基特淋巴瘤（BL）细胞中，由于t（8;14）染色体易位，c-myc通常位于IG基因座的E μ增强子附近并上调。我们证明，在BL细胞中的肽核酸（PNA），互补的内含子E μ序列（PNAE μ wt），特异性地阻断下的E μ增强子控制的c-myc癌基因的表达，并抑制BL细胞在培养中的生长。在这里，我们研究了PNAE μ wt是否也能够阻断用人BL细胞系接种的SCID小鼠中的肿瘤生长。在小鼠皮下接种后，BL细胞可重复地形成肿瘤。在接种前用PNAE μ wt预处理BL细胞和向已经接种BL细胞的小鼠长期静脉内施用PNAE μ wt选择性地引起肿瘤出现的潜伏期增加和最终肿瘤大小减小。PNAE μ wt处理的动物的肿瘤显示出大量的细胞坏死和c-myc下调区域。肿瘤生长的抑制是特异性的，并且在携带序列突变的PNAE mu mut和其中易位的c-myc不受E mu增强子控制的BL细胞系中未观察到。这些数据证实了靶向调节非编码区的PNA的潜在治疗价值。
In Burkitt's lymphoma (BL) cells due to a t(8;14) chromosomal translocation c-myc is often placed in proximity to the E mu enhancer of the Ig locus and upregulated. We demonstrated that in BL cells a peptide nucleic acid (PNA), complementary to intronic E mu sequences (PNAE mu wt), specifically blocks the expression of the c-myc oncogene under the E mu enhancer control and inhibits BL cell growth in culture. Here, we investigated whether PNAE mu wt was also able to block tumor growth in SCID mice inoculated with human BL cell lines. After subcutaneous inoculum in mice BL cells reproducibly form tumors. Both pre-treatment of BL cells with PNAE mu wt before inoculum and chronic intravenous administration of PNAE mu wt to mice already inoculated with BL cells selectively caused increased latency of tumor appearance and decreased final tumor size. Tumors from PNAE mu wt-treated animals showed substantial areas of cell necrosis and of c-myc downregulation. Inhibition of tumor growth was specific and was not observed with PNAE mu mut carrying sequence mutations and in BL cell lines where the translocated c-myc is not under the control of the E mu enhancer. These data confirm the potential therapeutic value of PNA targeted to regulatory non-coding regions.