The potential of clusterin inhibiting antisense oligodeoxynucleotide therapy for prostate cancer.
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.
Miyake
Hideaki
H
Hyogo Medical Center for Adults, Department of Urology, 13-70 Kitaohji-cho, Akashi 673-8558, Japan. hideakimiyake@hotmail.com
Hara
Isao
I
Fujisawa
Masato
M
Gleave
Martin E
ME
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D051152:Clusterin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D000970:Antineoplastic Agents; D051152:Clusterin; D016376:Oligonucleotides, Antisense