Chemosensitization and delayed androgen-independent recurrence of prostatecancer with the use of antisense Bcl-2 oligodeoxynucleotides

Background: Increased expression of the bcl-2 gene has been observed in pro state cancer cells after androgen withdrawal and has been associated with t he development of androgen independence and chemoresistance. The objective of this study was to determine whether antisense Bcl-2 oligodeoxy-nucleotid es could enhance paclitaxel cytotoxicity and delay androgen-independent pro gression. Methods: Northern and western blot analyses were used to measure changes in Bcl-2 expression in mouse Shionogi tumor cells after treatment w ith antisense Bcl-2 oligodeoxynucleotides and/or paclitaxel, Growth inhibit ion and induction of apoptotic cell death were assessed with the use of sta ndard methods. All P values are two-sided, Results: Treatment of Shionogi t umor cells with 500 nM antisense Bcl-2 oligodeoxynucleotides decreased expr ession of Bcl-2 messenger RNA (mRNA) by approximately 85%, Paclitaxel treat ment induced Bcl-2 protein phosphorylation but did not alter Bcl-2 mRNA exp ression. Antisense Bcl-2 oligodeoxynucleotide treatment substantially enhan ced paclitaxel chemosensitivity in a dose-dependent manner. Characteristic apoptotic DNA laddering and cleavage of poly(adenosine diphosphate-ribose) polymerase were demonstrated only after combined treatment, Adjuvant in viv o administration of antisense Bcl-2 oligodeoxynucleotides and micellar pacl itaxel following castration resulted in a statistically significant delay o f androgen-independent, recurrent tumors compared with administration of ei ther agent alone (P < .001, Mantel-Cox log-rank test). Combination therapy also statistically significantly inhibited the growth of established hormon e-refractory tumors compared with treatment with either agent alone (P < .0 01, Student's t test). Conclusions, Combined treatment with antisense Bcl-2 oligodeoxynucleotides and paclitaxel could be a novel and attractive strat egy to inhibit progression to androgen-independent disease as well as growt h of hormone-refractory prostate cancer through deprivation of Bcl-2 functi on.