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Introduction to Gene Function

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CancerQuest > Introduction to Patient Information > An Introduction to Cancer Treatments > Targeted Therapy > Antisense Oligonucleotides

Antisense Oligonucleotides

As discussed in detail in the section on Cell Function, our genes consist of long strings of nucleotides along the DNA in our chromosomes. When there is a requirement for any particular gene to be expressed, the process of transcription leads to the production of an mRNA message from that gene.

Unlike the double-stranded structure of DNA, messenger RNA molecules are single-stranded. Like DNA molecules, these single-stranded RNA molecules are capable of binding to complementary nucleic acid strands. Therefore, if another single stranded string of nucleic acid bases with a sequence complementary to the sequence of a given mRNA (the antisense sequence) enters the cell, it will bind to that specific mRNA and inactivate it. The bound mRNA is not suitable for translation and is degraded.

Antisense oligonucleotide drugs are one of the newer areas of drug development. This technology offers researchers the ability to target almost any cellular process with complete specificity. If a protein is helping a cancer cell to grow, then the appropriate antisense oligonucleotide could be used to prevent that protein from ever being made. Because antisense oligonucleotides are so specific, it is unlikely that any other protein in the body would be affected. This specificity should result in a reduction of the side effects often seen with conventional cancer treatments.⁽¹⁾

The function of antisense RNA is shown in the animation below. The first part of the animation depicts the normal translation process of the mRNA (purple) and the second part shows the binding of an antisense RNA (red) to the mRNA (purple) leading to a blockage of protein production.

The full mechanism of this inactivation is not entirely understood, but it may be related to the fact that double stranded RNA occurs only rarely in normal cells. Since the instructions to make each protein are carried by a unique mRNA, these messages can be individually inactivated or "knocked out" by these complementary sequences.⁽¹⁾

No antisense cancer drugs have been approved by the FDA but many clinical trials are underway testing a agents directed against different targets and  in different cancer types.^(2)(3)(4)

View a list of clinical trials involving antisense drugs (NCI).

References for this page:

1. Isis Pharmaceuticals [http://www.isip.com]
2. Caruso G, Caffo M, Raudino G, Alafaci C, Salpietro FM, Tomasello F. Antisense oligonucleotides as innovative therapeutic strategy in the treatment of high-grade gliomas. Recent Pat CNS Drug Discov. 2010 Jan;5(1):53-69. [PUBMED]
3. Cassell A, Grandis JR. Investigational EGFR-targeted therapy in head and neck squamous cell carcinoma. Expert Opin Investig Drugs. 2010 Jun;19(6):709-22. [PUBMED]
4. Patel MP, Masood A, Patel PS, Chanan-Khan AA. Targeting the Bcl-2. Curr Opin Oncol. 2009 Nov;21(6):516-23. [PUBMED]