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Antisense of oligonucleotides and the inhibition of oncogene expression
J Prins1, E G de Vries, N H Mulder
1Department of Internal Medicine, University Hospital Groningen, The Netherlands.
Abstract:
Inhibition of oncogenes represents a new strategy that might lead to a better understanding of the different steps involved in tumorigenesis and also to the development of new therapeutic approaches. Attempts have been made to interfere with gene expression by in situ generation of mRNA from recombinant vectors (antisense RNA) or by the exogenous introduction of synthetic oligonucleotides (antisense oligonucleotides). Antisense oligonucleotides can inhibit the expression of specific genes by blocking the translation after hybridization with the target mRNAs--the antisense strategy. Antisense oligonucleotides can also be targeted to specific sequences of the DNA double helix. This causes inhibition of transcription--the antigene strategy. Regulatory sequences involved in controlling the transcription of oncogenes are used as targets for this type of 'antigene' oligonucleotide. Both strategies can be applied to control the oncogene expression of tumour cells in tissue culture, as exemplified in this review by myc antisense oligonucleotides. Recently the antisense strategy is moving into the area of clinical trials, aimed at curing chronic myelogenous leukaemia by ex vivo bone marrow purging. However, many difficulties have still to be overcome before the application of antisense oligonucleotides can be evaluated in the treatment of cancer.
Insights
Antisense oligonucleotides offer a novel strategy for controlling oncogene expression in cancer. While promising for therapeutic development, challenges remain before widespread clinical application for cancer treatment.
Area of Science:
- Molecular biology
- Cancer research
- Gene therapy
Background:
- Oncogene inhibition is a novel strategy for understanding tumorigenesis and developing cancer therapeutics.
- Antisense RNA and antisense oligonucleotides are methods to interfere with gene expression.
- Antisense strategies target messenger RNA (mRNA) or DNA to inhibit gene expression.
Purpose of the Study:
- To review the antisense and antigene strategies for controlling oncogene expression.
- To discuss the application of antisense oligonucleotides in cancer research and therapy.
- To highlight the potential and challenges of antisense oligonucleotide-based cancer treatments.
Main Methods:
- Antisense strategy: Hybridization of antisense oligonucleotides with target mRNAs to block translation.
- Antigene strategy: Targeting DNA sequences with oligonucleotides to inhibit transcription.
- Application in tissue culture: Using antisense oligonucleotides (e.g., myc) to control oncogene expression in tumor cells.
Main Results:
- Both antisense and antigene strategies demonstrate potential for controlling oncogene expression in vitro.
- Antisense oligonucleotides have shown promise in preclinical and early clinical settings, such as ex vivo bone marrow purging for chronic myelogenous leukemia.
- The review exemplifies the use of myc antisense oligonucleotides in controlling tumor cell oncogene expression.
Conclusions:
- Antisense oligonucleotides represent a promising therapeutic avenue for cancer treatment by targeting oncogene expression.
- The clinical application of antisense oligonucleotides in cancer therapy is advancing, with some strategies entering clinical trials.
- Significant challenges must be addressed to fully realize the potential of antisense oligonucleotides in cancer treatment.