Morpholino antisense oligomer targeting human midkine: Its application for cancer therapy
Morpholino antisense oligomer targeting human midkine: Its application for cancer therapy
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DOI：
10.1002/ijc.20781
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发表时间：
2005-04-10
影响因子：
6.4
通讯作者：
Muramatsu, T
中科院分区：
文献类型：
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作者：
Takei, Y;Kadomatsu, K;Muramatsu, T
肝素结合生长因子中期因子（MK）的过表达已在许多恶性肿瘤中观察到，使其成为有吸引力的治疗靶点。我们使用吗啉代反义寡聚体下调人MK在人前列腺（PC-3）和结肠癌（SW 620）细胞中的表达，并确定这种抗癌治疗的实际优势。针对MK的吗啉代反义寡聚体引起靶蛋白水平的显著和序列特异性的降低，导致转染细胞的生长和锚定非依赖性生长的抑制。此外，MK吗啉代反义寡聚体在PC-3-和SW 620-异种移植模型中表现出显著的抗癌作用。与硫代修饰的寡聚脱氧核苷酸相比，吗啉代寡聚脱氧核苷酸具有稳定性好和无毒性两大优点。MALDI-TOF质谱分析表明，吗啉代反义寡聚体在血清核酸酶存在下完全稳定。血清学检查表明MK吗啉代反义寡聚体无毒性。我们的研究表明，抑制MK表达的吗啉代反义寡聚体是一个有前途的新的和安全的治疗癌症的策略。(C)2004 Wiley-Liss，Inc.
Overexpression of a heparin-binding growth factor, midkine (MK), has been observed in many malignancies, making it an attractive therapeutic target. We used morpholino antisense oligomers to downregulate human MK expression in human prostate (PC-3) and colon carcinoma (SW620) cells, and determined the practical advantages of this anticancer therapeutic. Morpholino antisense oligomers directed against MK caused a dramatic and sequence-specific decrease of the target protein level, resulting in the inhibition of growth and anchorage-independent growth of the transfected cells. Furthermore, MK morpholino antisense oilgomers exhibited a significant anticancer effect in the PC-3- and SW620-xenograft models. In comparison with phosphorothioate-modified oligodeoxynucleotide, morpholino oligomers showed 2 major advantages, stability and non-toxicity. MALDI-TOF mass spectrometric analysis showed that morpholino antisense oligomers were completely stable in the presence of serum nuclease(s). Serological examinations demonstrated no toxicity of MK morpholino antisense oligomers. Our study indicates that inhibition of MK expression by morpholino antisense oligomer is a promising novel and safe therapeutic strategy for cancers. (C) 2004 Wiley-Liss, Inc.