Tumor regression by combination antisense therapy against Plk1 and Bcl-2
Tumor regression by combination antisense therapy against Plk1 and Bcl-2
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DOI：
10.1038/sj.onc.1206038
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发表时间：
2003-01-09
期刊：
影响因子：
8
通讯作者：
Zeuzem, S
中科院分区：
文献类型：
--
作者：
Elez, R;Piiper, A;Zeuzem, S
在不同的人类恶性肿瘤中观察到细胞增殖相关的 Polo 样激酶 1 (PLK1) 和细胞凋亡相关的 BCL-2 基因表达增加。抑制细胞增殖和重新激活细胞凋亡是抗癌治疗的基本原则。这种方法的效率通常受到抗癌药物靶向和递送到肿瘤中的不足的限制。通过尾静脉将针对 PLK1 和 BCL-2 的硫代磷酸反义寡脱氧核苷酸 (ODN) 全身施用到携带 A549、MDA-MB-435 和 Detroit562 异种移植物的裸鼠中。为了增强肿瘤特异性摄取并降低反义ODN的全身毒性，在体内应用了膜电穿孔转移。 Northern 和 Western blot 分析用于评估 PLK1 和 BCL-2 表达。切除肿瘤后评估肿瘤质量。所有三种细胞系和相应的异种移植物均表达高水平的 PLK1，并且对反义 PLK1 处理敏感。反义BCL-2疗法对表达高水平BCL-2的肿瘤有效，但对表达低水平BCL-2的A549细胞和相应的异种移植物无效。在膜电穿孔转移的支持下，以 5mg/kg 的剂量每周两次施用反义 ODN，消除了 60-100% 的异种移植肿瘤。 BCL-2 和 PLK1 联合治疗在过表达 BCL-2 的 MDA-MB-435 细胞中具有协同抗肿瘤作用。这项研究提供的证据表明，针对增殖和促生存相关靶标的反义ODN的全身给药与肿瘤体内电穿孔的组合代表了一种有前途的抗肿瘤治疗方法。
Increased expression of the cell proliferation-associated polo-like kinase 1 (PLK1) and apoptosis-associated BCL-2 genes has been observed in different human malignancies. Inhibition of cell proliferation and reactivation of apoptosis are basic principles in anticancer therapy. The efficiency of this approach is often limited by insufficient targeting and delivery of anticancer drugs into the tumors. Phosphorothioate antisense oligodeoxynucleotides (ODNs) directed against PLK1 and BCL-2 were administered systemically via the tail vein into nude mice bearing A549, MDA-MB-435, and Detroit562 xenografts. To enhance tumor-specific uptake and to reduce systemic toxicity of antisense ODNs membrane electroporation transfer was applied in vivo. Northern and Western blot analyses were used to assess PLK1 and BCL-2 expression. Tumor mass was assessed after resection of tumors. All three cell lines and corresponding xenografts expressed high levels of PLK1 and were sensitive towards antisense PLK1 treatment. Antisense BCL-2 therapy was effective in tumors expressing high levels of BCL-2, but not in A549 cells and corresponding xenografts, which express low levels of BCL-2. Administration of antisense ODNs in a dose of 5mg/kg, twice weekly during four weeks supported by the membrane electroporation transfer, eradicated 60-100% of the xenografted tumors. Antitumor effect in BCL-2 overexpressing MDA-MB-435 cells was synergistic for BCL-2 and PLK1 combination therapy. This study provides evidence that combined systemic administration of antisense ODNs against proliferation and pro- survival associated targets and in vivo electroporation of tumors represents a promising antitumor therapeutic approach.