Miyake Hideaki, Hara Isao, Gleave Martin E
The Prostate Center, Vancouver General Hospital, Vancouver, Canada.
Int J Urol. 2005 Sep;12(9):785-94. doi: 10.1111/j.1442-2042.2005.01173.x.
The objective of this study was to review our experience in the development of antisense (AS) oligodeoxynucleotide (ODN) therapy for prostate cancer targeting antiapoptotic gene, clusterin.
We initially summarized our data demonstrating that clusterin could be an optimal therapeutic target for prostate cancer, then presented the process of developing AS ODN therapy using several preclinical animal models. Finally, the preliminary data of the recently completed phase I clinical trial using AS clusterin ODN as well as the future prospects of this therapy are discussed.
Expression of clusterin was highly up-regulated after androgen withdrawal and during progression to androgen-independence, but low or absent in untreated tissues in both prostate cancer animal model systems and human clinical specimens. Introduction of the clusterin gene into human prostate cancer cells confers resistance to several therapeutic stimuli, including androgen ablation, chemotherapy and radiation. AS ODN targeting the translation initiation site of the clusterin gene markedly inhibited clusterin expression in prostate cancer cells in a dose-dependent and sequence-specific manner. Systemic treatment with AS clusterin ODN enhanced the effects of several conventional therapies through the effective induction of apoptosis in prostate cancer xenograft models. Based on these findings, a phase I clinical trial was completed using AS clusterin ODN incorporating 2'-O-(2-methoxy)ethyl-gapmer backbone (OGX-011), showing up to 90% suppression of clusterin in prostate cancer.
The data described above identified clusterin as an antiapoptotic gene up-regulated in an adaptive cell survival manner following various cell death triggers that helps confer a phenotype resistant to therapeutic stimuli. Inhibition of clusterin expression using AS ODN technology enhances apoptosis induced by several conventional treatments, resulting in the delay of AI progression and improved survival. Clinical trials using AS ODN confirm potent suppression of clusterin expression and phase II studies will begin in early 2005.
本研究的目的是回顾我们在开发针对抗凋亡基因聚集素的反义（AS）寡脱氧核苷酸（ODN）前列腺癌治疗方法方面的经验。
我们首先总结了数据，证明聚集素可能是前列腺癌的最佳治疗靶点，然后介绍了使用几种临床前动物模型开发AS ODN治疗方法的过程。最后，讨论了最近完成的使用AS聚集素ODN的I期临床试验的初步数据以及该治疗方法的未来前景。
在雄激素撤除后以及向雄激素非依赖性进展过程中，聚集素的表达高度上调，但在前列腺癌动物模型系统和人类临床标本的未治疗组织中表达低或无表达。将聚集素基因导入人前列腺癌细胞可使其对多种治疗刺激产生抗性，包括雄激素剥夺、化疗和放疗。靶向聚集素基因翻译起始位点的AS ODN以剂量依赖性和序列特异性方式显著抑制前列腺癌细胞中聚集素的表达。在前列腺癌异种移植模型中，用AS聚集素ODN进行全身治疗通过有效诱导凋亡增强了几种传统疗法的效果。基于这些发现，使用包含2'-O-（2-甲氧基）乙基间隙聚物骨架（OGX-011）的AS聚集素ODN完成了I期临床试验，显示前列腺癌中聚集素的抑制率高达90%。
上述数据确定聚集素是一种抗凋亡基因，在各种细胞死亡触发因素后以适应性细胞存活方式上调，有助于赋予对治疗刺激具有抗性的表型。使用AS ODN技术抑制聚集素表达可增强几种传统治疗诱导的凋亡，导致雄激素非依赖性进展延迟并改善生存率。使用AS ODN的临床试验证实了对聚集素表达的有效抑制，II期研究将于2005年初开始。
