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Published on: April 3, 2018
Antisense strategies for oncogene inactivation
C A Stein1, Luba Benimetskaya, S Mani
1Department of Oncology, Albert Einstein-Montefiore Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10467, USA. cstein@montefiore.org
Abstract:
Antisense oligonucleotides have been evaluated as antineoplastic agents in a series of clinical trials, with mixed results. However, phase III trials incorporating G3139, a phosphorothioate oligomer targeted to the initiation codon region of the bcl-2 mRNA, have recently been completed in advanced melanoma, myeloma, and chronic lymphocytic leukemia (CLL). This article discusses the mechanism of the antisense effect and its dependence on the cellular internalization of oligonucleotides and the activity of RNase H. It also describes the properties, specific and nonspecific, of phosphorothioate oligonucleotides, the predominant species in current clinical trials, and discusses pharmacokinetic data obtained from earlier phase I and II trials employing these molecules. While the application of antisense technology to the treatment of human cancer is conceptually straightforward, in practice there are many complicated, mechanistically based questions that must be considered.
Insights
Antisense oligonucleotides, including G3139 targeting bcl-2 mRNA, show potential as cancer treatments. Further research is needed to address complexities in their clinical application for advanced melanoma, myeloma, and chronic lymphocytic leukemia.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Antisense oligonucleotides (ASOs) are being investigated as cancer therapeutics.
- G3139, a phosphorothioate oligomer targeting bcl-2 mRNA, has undergone Phase III clinical trials for advanced cancers.
- Previous trials yielded mixed results, necessitating a deeper understanding of ASO mechanisms.
Purpose of the Study:
- To review the mechanism of antisense effect, including cellular uptake and RNase H activity.
- To describe the properties of phosphorothioate oligonucleotides used in clinical trials.
- To discuss pharmacokinetic data from earlier phase I and II trials.
Main Methods:
- Review of existing clinical trial data (Phase I, II, and III).
- Analysis of the mechanism of action for antisense oligonucleotides.
- Examination of physicochemical properties of phosphorothioate oligonucleotides.
Main Results:
- Phase III trials of G3139 in advanced melanoma, myeloma, and chronic lymphocytic leukemia (CLL) have been completed.
- The efficacy of antisense oligonucleotides is dependent on cellular internalization and RNase H activity.
- Phosphorothioate oligonucleotides exhibit specific and nonspecific properties.
Conclusions:
- Antisense technology offers a conceptually simple approach to cancer treatment.
- Practical application involves complex, mechanistically based challenges.
- Further investigation is required to optimize antisense oligonucleotide therapy for various cancers.
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