Oligonucleotides as Anticancer Agents: From the Benchside to the Clinic and Beyond
Abstract:Prevention, improved screening, and better treatment regimens have improved cancer incidence and mortality in the last decade. Chemoradiation continues to cause high morbidity in patients undergoing treatment. DNA therapeutics have the potential to modify the genes that cause tumor progression in order to produce a response that is tumor-specific, efficacious and systemic without toxicity to normal cells.
The most widely used and most experimentally advanced DNA therapeutic is the antisense oligonucleotide. These oligomers are predominantly used to inhibit mRNA expression. For cancer chemotherapy, the Bcl-2 antisense oligonucleotide is currently in phase III clinical trials.
Transcription factor decoys form DNA:protein heteroduplexes and produce cellular responses at the genomic rather than transcriptional level. The use of other transcription factor decoys as oncologic reagents is now being developed.
The phenomenon of RNA interference has only recently been discovered to occur in plants as a response to viral infection. Small interfering RNAs cause mRNA inhibition. siRNAs also inhibit expression of mRNA, however the intracellular cascade is quite different. siRNA could prove to be more powerful and longer lasting than antisense. Several DNA therapeutics are currently being studied. This review will focus on antisense oligonucleotides, transcription factor decoys and siRNA with an emphasis on how they can be employed as anticancer agents. Mechanism of action and design strategies will be summarized, as well as therapeutic targets and demonstrated clinical efficacy for each reagent.
Document Type: Review Article
Affiliations: Departments of Otolaryngology (JRG, FMC) and Pharmacology (JRG), University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Publication date: 2005-08-01
- Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.
Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.