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Published on: May 16, 2020
Oligonucleotides as anticancer agents: from the benchside to the clinic and beyond
Francesca Marietta Coppelli1, Jennifer Rubin Grandis
1Department of Otolaryngology, University of Pittsburgh School of Medicine, Cancer Institute, Pittsburgh, PA 15213, USA.
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.
Insights
DNA therapeutics like antisense oligonucleotides and small interfering RNAs offer targeted cancer treatment with reduced toxicity. These novel agents modify genes to specifically combat tumors, improving efficacy and patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cancer treatment advances include prevention, screening, and improved regimens, yet chemoradiation causes significant morbidity.
- DNA therapeutics offer a promising approach for tumor-specific, efficacious, and systemic cancer treatment with minimal toxicity to normal cells.
Purpose of the Study:
- This review focuses on DNA therapeutics, specifically antisense oligonucleotides, transcription factor decoys, and small interfering RNAs (siRNAs).
- The aim is to explore their application as anticancer agents, summarizing mechanisms, design strategies, therapeutic targets, and clinical efficacy.
Main Methods:
- Review of current literature on DNA therapeutics in oncology.
- Focus on antisense oligonucleotides, transcription factor decoys, and siRNAs.
- Analysis of mechanisms of action, design strategies, and therapeutic targets.
Main Results:
- Antisense oligonucleotides inhibit mRNA expression, with Bcl-2 antisense oligonucleotide in Phase III trials.
- Transcription factor decoys create DNA:protein heteroduplexes, acting at the genomic level.
- Small interfering RNAs (siRNAs) also inhibit mRNA expression via a different intracellular cascade, potentially offering greater potency and longevity than antisense.
Conclusions:
- DNA therapeutics represent a significant advancement in cancer treatment, offering targeted gene modification.
- Antisense oligonucleotides, transcription factor decoys, and siRNAs show potential as effective anticancer agents.
- Further research and clinical trials are essential to fully realize the therapeutic potential of these novel DNA-based strategies.
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