Synergistic chemosensitization and inhibition of progression to androgen independence by antisense Bcl-2 oligodeoxynucleotide and paclitaxel in the LNCaP prostate tumor model.
Bcl-2 expression is up-regulated in prostate cancer cells after androgen ablation and associated with development of androgen independence and chemoresistance. We recently reported that antisense Bcl-2 oligodeoxynucleotides (ODNs) delay progression to androgen independence in the androgen-dependent (AD) human LNCaP prostate tumor model. The objectives in this study were to determine whether antisense human Bcl-2 ODN enhances chemosensitivity of paclitaxel and whether combined antisense Bcl-2 ODN and paclitaxel further delays time to androgen-independent (AI) progression in the LNCaP tumor model. Semi-quantitative reverse transcriptast-polymerase chain reaction revealed that treatment of LNCaP cells with antisense Bcl-2 ODN decreased Bcl-2 expression in a dose-dependent and sequence-specific manner, whereas Bcl-2 expression was not affected by paclitaxel treatment. Antisense Bcl-2 ODN treatment significantly enhanced paclitaxel chemosensitivity in vitro, reducing cell viability after treatment with 1 nM paclitaxel from 76% to 42%. Characteristic apoptotic DNA laddering was demonstrated after combined treatment with 500 nM antisense Bcl-2 ODN and 1 nM paclitaxel but not with either agent alone. Adjuvant in vivo administration of combined antisense Bcl-2 and polymeric micellar paclitaxel after castration resulted in a significant delay of emergence of AI recurrent LNCaP tumors compared with either agent alone. By 15 weeks post castration, tumor volume in mice treated with antisense Bcl-2 ODN alone or mismatch control ODN plus paclitaxel was >3-fold higher than in mice treated with combined antisense Bcl-2 ODN and paclitaxel. Mean serum prostate-specific antigen levels returned to or were above precastration levels by 11 weeks post castration in mice treated with antisense Bcl-2 ODN alone or mismatch control ODN plus paclitaxel but remained 90% below the pre-castration level in mice treated with combined antisense Bcl-2 ODN and paclitaxel. These findings identify combined antisense Bcl-2 and paclitaxel as a potentially new therapeutic strategy for advanced prostate cancer by enhancing paclitaxel chemosensitivity and delaying progression of hormone-refractory prostate cancer.
The Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
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S
Leung
H
H
Miyake
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T
Zellweger
A
A
Tolcher
M E
ME
Gleave
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D017931:DNA Primers / Q000737:chemistry; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D017239:Paclitaxel / Q000627:therapeutic use*; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000728:Androgens; D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D017430:Prostate-Specific Antigen; D017239:Paclitaxel