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Titolo:
Use of antisense oligonucleotides targeting the antiapoptotic gene, clusterin/testosterone-repressed prostate message 2, to enhance androgen sensitivity and chemosensitivity in prostate cancer
Autore:
Gleave, ME; Miyake, H; Zellweger, T; Chi, K; July, L; Nelson, C; Rennie, P;
Indirizzi:
Univ British Columbia, Div Urol, Vancouver, BC V5Z 3J5, Canada Univ British Columbia Vancouver BC Canada V5Z 3J5 ver, BC V5Z 3J5, Canada Vancouver Gen Hosp, Prostate Ctr, Vancouver, BC, Canada Vancouver Gen Hosp Vancouver BC Canada ostate Ctr, Vancouver, BC, Canada
Titolo Testata:
UROLOGY
fascicolo: 2A, volume: 58, anno: 2001, supplemento:, S
pagine: 39 - 48
SICI:
0090-4295(200108)58:2A<39:UOAOTT>2.0.ZU;2-D
Fonte:
ISI
Lingua:
ENG
Soggetto:
APOLIPOPROTEIN-J CLUSTERIN; NECROSIS-FACTOR-ALPHA; RAT VENTRAL PROSTATE; SHIONOGI TUMOR-MODEL; PHASE-II TRIAL; CELL-DEATH; IN-VITRO; SULFATED GLYCOPROTEIN-2; ADJUVANT TREATMENT; ORAL ESTRAMUSTINE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Citazioni:
69
Recensione:
Indirizzi per estratti:
Indirizzo: Gleave, ME Univ British Columbia, Div Urol, D-9,2733 Heather St, Vancouver, BC V5Z 3J5, Canada Univ British Columbia D-9,2733 Heather St Vancouver BCCanada V5Z 3J5
Citazione:
M.E. Gleave et al., "Use of antisense oligonucleotides targeting the antiapoptotic gene, clusterin/testosterone-repressed prostate message 2, to enhance androgen sensitivity and chemosensitivity in prostate cancer", UROLOGY, 58(2A), 2001, pp. 39-48

Abstract

Background: Androgen resistance develops, in part, from upregulation of antiapoptotic genes after androgen withdrawal. Identification and targeting of genes mediating androgen-independent (AI) progression may lead to development of novel therapies that delay hormone-refractory prostate cancer. Clusterin is a cell survival gene, that increases after androgen ablation. Here, we review clusterin's functional role in apoptosis and the ability of antisense oligonucleotides (ASOs) against clusterin to enhance apoptosis in prostate cancer xenograft models. Results: Immunostaining of radical prostatectomy specimens confirm that clusterin is highly expressed in 80% prostate cancer cells after neoadjuvant hormone therapy, but is low or absent (< 20%) in untreated specimens. Clusterin levels increase > 10 fold in regressing Shionogi tumors after castration. Pretreatment of mice bearing androgen-dependent Shionogi tumors with calcium antagonists inhibited castration-induced apoptosis, tumor regression,and clusterin gene upregulation, illustrating that clusterin is an apoptosis-associated gene and not an androgen-repressed gene. Clusterin ASOs reduced clusterin levels in a Close-dependent and sequence-specific manner. Adjuvant treatment with murine clusterin ASOs after castration of mice bearing Shionogi tumors decreased clusterin levels by 70% and resulted in earlier onset and more rapid apoptotic tumor regression, with significant delay in recurrence of Al tumors. Species-specific clusterin ASOs also increased the cytotoxic effects of paclitaxel, reducing the 50% inhibitory concentration (IC50) of PC-3 and Shionogi cells by 75% to 90%. Although clusterin ASOs had no effect on the growth of established Al Shionogi or PC-3 tumors, clusterin ASOs synergistically enhanced paclitaxel-induced tumor regression in both Shionogi and PC-3 models. Conclusions: Collectively, these data identify clusterin as an antiapoptosis protein, upregulated in an adaptive cell-survival manner by androgen ablation and chemotherapy, which confers resistance to various cell-death triggers. Inhibition of clusterin upregulation using clusterin ASOs can enhancecell death after treatment with androgen ablation and chemotherapy. (C) 2001, Elsevier Science Inc.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/09/20 alle ore 02:45:45