The role of antisense oligonucleotides in the treatment of bladder cancer

Abstract

Both intravesical and systemic chemotherapy are limited in their efficacy in the treatment of bladder cancer patients. These limitations are centred around an inability to induce apoptosis in bladder tumour cells. This resistance to apoptosis induction is commonly associated with the overexpression of antiapoptotic proteins such as Bcl-2. Strategies to decrease the cellular expression of such proteins would enhance chemotherapy effectiveness. One such strategy is to use antisense oligonucleotides which are short sequence specific single stranded DNA or RNA molecules designed to bind to the RNA of the target protein. By binding to the target RNA, protein production is interrupted and target protein levels decease. When used to target antiapoptotic proteins, antisense oligonucleotides can therefore be used as a pre-treatment before chemotherapy to help chemosensitise the tumour cell. This review outlines the rationale for this strategy and the work done to date with antisense oligonucleotides in bladder cancer.

Comparative Study of Apoptotic Antitumor Effect between Angiogenesis Inhibitor AGM-1470 and MVAC Chemotherapy on Rat Urinary Bladder Cancer

“…No previous report has addressed the direct effect of MVAC therapy on bcl-2 status in tumor cells. However, bcl-2 overexpression in bladder tumor cells has been characterized as being chemo-resistant, and the role of antisense oligonucleotides of bcl-2 in the treatment of bladder cancer is currently under consideration for use in a new potent therapeutic strategy [24]. Our study demonstrated a significant anti-apoptotic effect of bcl-2 protein in the AGM-1470-treated group, and we found the same tendency in the MVAC-treated group.…”

Hsp27 knockdown using nucleotide-based therapies inhibit tumor growth and enhance chemotherapy in human bladder cancer cells

“…The accessibility of the bladder mucosa and the low systemic absorption through the bladder wall make intravesical therapy an excellent route of administration of ASO. Although no studies have yet been reported that assess pharmacokinetic and pharmacodynamic activity of ASO after intravesical delivery in humans, preclinical studies would suggest that ASO are taken up by urothelium (47,48). Interestingly, the only approved clinical indication for an ASO is for intravitreal injection of cytomegalovirus-induced retinitis in human immunodeficiency virus, illustrating the potential clinical utility of local instillation for this class of therapeutics (49).…”

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

“…Despite very high transfection rates of UMUC-3 cells in vitro, we observed limited in vivo penetration of AS-ODNs. Inconsistent Wndings on AS-ODN delivery and uptake have been published, depending on the type of tumors, malignant potential and experimental setting (Duggan et al 2002;Kunze et al 2008;Zhao et al 1998). In a recent report nucleic acid penetration into heterotopic UC was achieved, but predominantly present in the peripheral areas of the tumor (Kunze et al 2008).…”