Antisense oligonucleotides in the treatment of bladder cancer

Abstract

This review examines the role that antisense oligonucleotides play in the treatment of superficial and muscle-invasive bladder cancer. The unique environment of the urinary bladder allows intravesical instillation of antisense oligonucleotides, and researchers have already demonstrated uptake of antisense oligonucleotides in models of bladder cancer. Second, proof of principle has been established by demonstrating downregulation of the antisense target mRNA and protein. Third, and most importantly from a therapeutic perspective, synergy between chemotherapy and antisense oligonucleotides has been shown in bladder cancer models in vitro and in vivo. The collective evidence points to a role for antisense oligonucleotides in the treatment of superficial and muscle-invasive bladder cancer in combination with existing treatment modalities.

Novel therapeutics in metastatic bladder cancer

“…In such terms, antisense oligonucleotide (AO) technology represents a viable strategy for bcl-2 protein downregulation; AOs are short, synthetic stretches of DNA that hybridise with specific mRNA strands corresponding to target genes. By binding to the mRNA, protein production is interrupted and target protein levels decease [92,93] . In experimental settings, combined AO therapy with conventional chemotherapeutic agents (cisplatin, adriamycin, mitomycin C, gemcitabine or paclitaxel) resulted in bcl-2 protein downregulation and synergistic cytotoxicity [94][95][96][97] .…”

In vivo evaluation of intravesical paclitaxel and combined bcl-xL antisense oligodeoxynucleotide treatment for orthotopic urothelial carcinoma

“…Multiple cancer-speciWc molecules have been targeted by AS-ODNs and chemosensitizing eVects have been reported for this approach (Glackin et al 2005;Hopkins-Donaldson et al 2003;Lebedeva et al 2001;Miyake et al 2004). We have described a signiWcant increase of UC cell death rates in a panel of UC cell lines when combining AS-ODNs targeting m-RNA that encodes for the antiapoptotic proteins bcl-2 and bcl-xL (Bolenz et al 2007a;Schaaf et al 2004).…”