Synthetic nucleic acids as potential therapeutic tools for treatment of bladder carcinoma

Abnormal gene activation in human tumours including bladder cancers (bCAs) may cause altered proliferation, maturation, and apoptosis as well as development of resistance to therapeutic interventions. Therefore, silencing of abnormally activated genes appears to be a rational approach for specific target-directed and sensitising therapies.

Of the available strategies for gene silencing, antisense-based techniques have attracted much attention and are the focus of this review. Putative target genes should be involved in essential tumour-promoting pathways, such as growth signalling, immortalisation, cell cycle regulation, apoptosis, angiogenesis, and development of therapy resistances. This review gives an overview of selected studies performed on bCA-derived cell lines and xenografts reporting down-regulation of potential target genes by antisense-based synthetic nucleic acids such as antisense oligodeoxynucleotides (AS-ODNs) and small interfering RNAs (siRNAs). Effects on proliferation of bCA cells and enhancement of the cytotoxic action of different chemotherapeutics were evaluated.

Knock-down of the selected target genes frequently caused an impairment of growth of different bCA cell lines originating from cell cycle arrest or increased apoptosis. In numerous studies, the pretreatment with AS-ODNs or siRNAs provoked strong enhancement of subsequent chemotherapies, emphasising the effectiveness of these inhibition approaches.

The application of antisense-based inhibitors in combination with chemotherapeutics might represent an alternative strategy for the adjuvant treatment of superficial bCA. Nevertheless, translation of this technology to the clinic might be hampered by inestimable off-target effects caused by AS-ODNs and their behaviour after intravesical instillation has to be evaluated in preclinical and clinical trials.