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Synergistic chemosensitization and inhibition of progression to androgen independence by antisense Bcl‐2 oligodeoxynucleotide and paclitaxel in the LNCaP prostate tumor model
Author(s) -
Leung Simon,
Miyake Hideaki,
Zellweger Tobias,
Tolcher Anthony,
Gleave Martin E.
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/1097-0215(200002)9999:9999<::aid-ijc1131>3.0.co;2-y
Subject(s) - lncap , paclitaxel , prostate cancer , cancer research , androgen , in vivo , medicine , biology , chemotherapy , cancer , hormone , microbiology and biotechnology
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. © 2001 Wiley‐Liss, Inc.