Antisense Technology: From Unique Laboratory Tool to Novel Anticancer Treatments

Antisense reagents and technology have developed as extraordinarily useful tools for the analysis of gene function. The capacity of antisense to reduce expression of RNA (including protein-encoding mRNA and noncoding RNA) important in a multitude of diseases has led to the concept of using antisense molecules as drugs to treat those diseases. Antisense oligonucleotides (ASOs) are being developed for this purpose, with single-stranded DNA ASOs currently the most advanced in clinical testing. Phase I to III clinical trials of ASOs are either completed or in progress for a number of diseases, including cancer. In this review, we focus on progress in developing antisense drugs to downregulate genes mediating malignant characteristics in tumors originating in multiple tissues. In addition, we review progress in (1) ASO targeting of microRNAs (miRNAs) to repress malignant characteristics in multiple tumor types including use of MT-AMOs (multiple-target anti-miRNA oligonucleotides); (2) combining ASOs with each other to generate “synthetic lethality” that enhances chemotherapeutic drug activity; (3) the use of RASONs (radiolabeled antisense ODNs) to image tumors for diagnostic purposes and to monitor therapeutic activity; (4) “on-target” and “off-target” effects of ASOs that lead to both decreases and increases in therapeutic benefit; (5) the chemistries of ASOs that enhance ASO stability, specificity, and activity and reduce undesirable toxicity; and (6) the relative advantages and disadvantages of RNAi-dependent and other ASOs for future application as therapeutic agents to diagnose, monitor, and treat cancer.