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 ab lation and associated with development of androgen independence and chemore sistance, 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 p aclitaxel and whether combined antisense Bcl-2 ODN and paclitaxel further d elays time to androgen-independent (Al) progression in the LNCaP tumor mode l. Semi-quantitative reverse transcriptast-polymerase chain reaction reveal ed that treatment of LNCaP cells with antisense Bcl-2 ODN decreased Bcl-2 e xpression in a dose-dependent and sequence-specific manner, whereas Bcl-2 e xpression was not affected by paclitaxel treatment. Antisense Bcl-2 ODN tre atment significantly enhanced paclitaxel chemosensitivity in vitro, reducin g cell viability after treatment with I nM paclitaxel from 76% to 42%. Char acteristic apoptotic DNA laddering was demonstrated after combined treatmen t with 500 nM antisense Bcl-2 ODN and I nM paclitaxel but not with either a gent, alone, Adjuvant in vivo administration of combined antisense Bcl-2 an d polymeric micellar paclitaxel after castration resulted in a significant delay of emergence of Al recurrent LNCaP tumors compared with either agent alone. By 15 weeks post castration, tumor volume in mice treated with antis ense Bcl-2 ODN alone or mismatch control ODN plus paclitaxel was >3-fold hi gher than in mice treated with combined antisense Bcl-2 ODN and paclitaxel, Mean serum prostate-specific antigen levels returned to or were above prec astration levels by II weeks post castration in mice treated with antisense Bcl-2 ODN alone or mismatch control ODN plus paclitaxel but remained 90% b elow the pre-castration level in mice treated with combined antisense Bcl-2 ODN and paclitaxel. These findings identify combined antisense Bcl-2 and p aclitaxel as a potentially new therapeutic strategy for advanced prostate c ancer by enhancing paclitaxel chemosensitivity and delaying progression of hormonerefractory prostate cancer. (C) 2001 Wiley-Liss, Inc.