Antisense Nucleotides

Antisense nucleotides are either ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) molecules that are complementary to a messenger RNA (mRNA) molecule. Because these molecules are complementary to given mRNA, they will bind to the RNA and form a free double-stranded mole­cule or double-stranded region of a chromosome. The double-stranded molecules are not able to interact with ribosomes and, as a result, a par­ticular protein is unable to be made. Inhibiting the production of a given protein may be important in the control and treatment of many diseases such as cancer.

Two approaches to antisense nucleotides have been tried: (1) direct in­troduction of antisense nucleotides into cells and (2) synthesis of antisense nucleotides within the cell. In the first approach, short antisense oligonu­cleotides are introduced directly into cells in hopes that they will interact with the appropriate mRNA. Scientists are using different nucleotides that are complementary to different regions of the mRNA—beginning, middle, or end—in an attempt to determine the most effective sequence.

Unfortunately, enzymes within cells often degrade these short oligonu­cleotides before they can interact with the target mRNA. Replacing the phosphate linkages in the nucleotides with sulfur or other linkages seems to prevent degradation.

The second approach involves using a vector (a vehicle for transferring genetic material) containing the entire gene to transfer DNA into the cells. This DNA will theoretically integrate into the chromosome, duplicate at each cell division, and remain within the cells. These vectors are constructed so that the control sequences for transcription are on the DNA strand op­posite to the one that is usually used for transcription. Therefore, when in­ducers are added, the cells make the antisense RNA, which then binds to mRNA from the normal gene. In many cases, the amount of an undesirable protein is reduced.

The use of antisense nucleotides is in its infancy, but the results have been promising in reducing certain types of cancer in animals. The proce­dure has the potential of becoming widely used in the future to treat a va­riety of diseases, provided that it has low risks associated with it.

References

Campbell, Neil A., Jane B. Reece, and Lawrence G. Mitchell. Biology, 5th ed. Menlo Park, CA: Benjamin Cummings, 1999.

Pasternak, Jack J. An Introduction to Human Molecular Genetics. Bethesda, MD: Fitzger­ald Science Press, Inc., 1999.