Targeting anti-apoptotic genes upregulated by androgen withdrawal using antisense oligonucleotides to enhance androgen- and chemo-sensitivity in prostate cancer.
The main obstacle to improved survival of advanced prostate cancer is our failure to prevent its progression to its lethal and untreatable stage of androgen independence. New therapeutic strategies designed to prevent androgen-independent (AI) progression must be developed before significant impact on survival can be achieved. Characterization of changes in gene expression profiles after androgen ablation and during progression to androgen-independence suggest that the various therapies used to kill neoplastic cells may precipitate changes in gene expression that lead to the resistant phenotype. Castration-induced increases in antiapoptosis genes, Bcl-2 and clusterin, help create a resistant phenotype, while antisense oligonucleotides can inhibit these adaptive cell survival mechanisms and enhance both hormone and chemotherapy. Ongoing efforts are necessary to identify additional molecular pathways mediating AI progression and chemoresistance, since complexities of tumor heterogeneity and adaptability dictate that optimal control over tumor progression will require multi-target systemic therapies.
Gleave
Martin E
ME
The Prostate Centre, Vancouver General Hospital, British Columbia, Canada.
Zellweger
Toby
T
Chi
Kim
K
Miyake
Hideaki
H
Kiyama
Satoshi
S
July
Laura
L
Leung
Simon
S
D000230:Adenocarcinoma / Q000473:pathology; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics*; D051152:Clusterin; D019254:Genes, bcl-2 / Q000235:genetics; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics; D016376:Oligonucleotides, Antisense; D017239:Paclitaxel / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000601:surgery / Q000628:therapy; D011944:Receptors, Androgen / Q000235:genetics; D013873:Thionucleotides; D015854:Up-Regulation / Q000235:genetics
D000972:Antineoplastic Agents, Phytogenic; C495242:CLU protein, human; D051152:Clusterin; D006023:Glycoproteins; D018832:Molecular Chaperones; D016376:Oligonucleotides, Antisense; D011944:Receptors, Androgen; D013873:Thionucleotides; D017239:Paclitaxel