Miyake Hideaki, Hara Isao, Fujisawa Masato, Gleave Martin E
Hyogo Medical Center for Adults, Department of Urology, 13-70 Kitaohji-cho, Akashi 673-8558, Japan.
Expert Opin Investig Drugs. 2006 May;15(5):507-17. doi: 10.1517/13543784.15.5.507.
This review summarise the authors' recent experience in the development of antisense (AS) oligodeoxynucleotide (ODN) therapy that targets a cytoprotective gene, clusterin, for the treatment of prostate cancer. The acquisition of resistance to a wide variety of proapototic stimuli was initially demonstrated by introducing the clusterin gene into prostate cancer cells. Furthermore, silencing clusterin expression using AS ODN synergistically enhanced the effects of several conventional therapeutic modalities through the effective induction of apoptosis in prostate cancer xenograft models. Based on these outcomes, Phase I clinical trials were conducted using AS clusterin ODN incorporating 2'-O-(2-methoxy)ethyl-gapmer backbone (OGX-011), and the optimal dose of OGX-011 capable of inducing </= 90% suppression of clusterin in human prostate cancer tissue was determined. Collectively, these findings suggest the utility of inactivating clusterin function using AS ODN technology as a novel therapeutic strategy for prostate cancer treatment. There have been four kinds of Phase II studies that have begun to further evaluate the efficacy of OGX-011 in patients with prostate, breast and lung cancers.
本综述总结了作者近期在开发反义（AS）寡脱氧核苷酸（ODN）疗法方面的经验，该疗法靶向一种细胞保护基因簇集蛋白，用于治疗前列腺癌。最初通过将簇集蛋白基因导入前列腺癌细胞，证明了其对多种促凋亡刺激产生抗性。此外，在前列腺癌异种移植模型中，使用AS ODN沉默簇集蛋白表达可通过有效诱导凋亡，协同增强几种传统治疗方式的效果。基于这些结果，开展了使用含2'-O-（2-甲氧基）乙基间隙mer骨架（OGX-011）的AS簇集蛋白ODN的I期临床试验，并确定了能够在人前列腺癌组织中诱导簇集蛋白抑制率≤90%的OGX-011最佳剂量。总体而言，这些发现表明，使用AS ODN技术使簇集蛋白功能失活作为一种治疗前列腺癌的新策略具有实用性。已经开展了四项II期研究，以进一步评估OGX-011对前列腺癌、乳腺癌和肺癌患者的疗效。
