title: Beyond simple castration: targeting the molecular basis of treatment resistance in advanced prostate cancer.
abstract: Over the past 20 years, research on hormonal treatments for prostate cancer focused on maximizing androgen ablation through combination therapy. Unfortunately, maximal androgen ablation increases treatment-related side effects and expense and has not significantly prolonged time to androgen-independent (AI) progression. Intermittent androgen suppression (IAS) is based on the hypothesis that if tumor cells surviving androgen withdrawal can be forced along a normal pathway of differentiation by androgen replacement, then apoptotic potential might be restored, androgen dependence may be prolonged and progression to androgen independence may be delayed. Observations from animal model studies suggest that progression to androgen independence is delayed by IAS and this strategy is now being evaluated in phase III trials. Another strategy for improving therapies in advanced prostate cancer involves targeting genes that are activated by either androgen withdrawal or chemotherapy to delay or prevent the emergence of the resistant AI phenotype. Targeted inhibition of stress-associated increases in gene expression precipitated by androgen withdrawal or chemotherapy may enhance treatment-induced apoptosis and delay progression to AI disease. Proteins fulfilling these criteria include antiapoptotic members of the Bcl-2 protein family, clusterin, Hsp27, and IGFBP-2 and IGFBP-5. The purpose of this paper is to review the rationale and progress in using targeted gene therapies to enhance tumor cell death after androgen withdrawal or taxane chemotherapy. Antisense oligonucleotides offer one approach to target genes involved in cancer progression, especially those not amenable to small molecule or antibody inhibition. The current status and future direction of several antisense oligonucleotides that have potential clinical use in cancer are also reviewed.
authors.affiliation: Vancouver General Hospital, D-9, 2733 Heather Street, Vancouver, BC, V5Z 3J5, Canada. gleave@interchange.ubc.ca
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.forename: Hideaki
authors.initials: H
authors.lastname: Miyake
authors.forename: Kim
authors.initials: K
authors.lastname: Chi
mesh_terms: D051152:Clusterin / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000628:therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D017211:Treatment Failure
chemical_list: D051152:Clusterin; D019253:Proto-Oncogene Proteins c-bcl-2