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Antisense Therapy for Cancer

© David Olle

What is antisense therapy?

Antisense therapy works at the genetic level to prevent mutated or overactive genes from directing the synthesis of proteins that are causing cancer. They are different from conventional drugs that are designed to interact with protein molecules after they are produced. Antisense drugs have a more selective action, and they have the potential to be more effective and less toxic than conventional drugs.

A Brief Review of Genes and Nucleic Acids (DNA and RNA)

Genes are the biological units of heredity, and exert their effect by directing the synthesis of a specific protein. Mutations in genes can be hereditary (passed on from generation to generation), or can occur during the lifetime of the person, such as the formation of a cancerous gene. Genes are composed of segments of deoxyribonucleic acid, or DNA. 4 DNA consists of two very long polynucleotides wound around each other in a double helix. The term polynucleotide indicates that it consists of a large number of nucleotide units. Each nucleotide consists of phosphate, the sugar deoxyribose, and one of four nucleic acid bases: adenine, thymine, guanine, or cytosine. In forming the double helix, the bases of one polynucleotide strand always link up in a complimentary fashion with the bases of the other strand. Wherever adenine appears on one strand, it is linked with thymine on the other strand. Similarly, guanine is linked with cytosine. The sequence of nucleotide bases in DNA determines the genetic code. The strand that is used as a template for the synthesis of ribonucleic acid (RNA) is known as the sense strand, while the other strand is known as the antisense strand. The double helix of DNA is closely bound with proteins to form chromosomes. In the transcription process, an enzyme (RNA polymerase) directs the synthesis of a single RNA polynucleotide that is complimentary to the DNA sense strand. The RNA strand differs from DNA in that the sugar is now ribose rather than deoxyribose, and the nucleic acid thymine is replaced by uracil. This RNA, called messenger RNA, is also known as a sense strand.

The Development of Antisense Drugs

An understanding of the complimentary pairing of nucleotide bases led the Harvard biochemist Paul Zamecnik 1 to develop the first antisense oligonucleotide in 1978. Oligo means “a few”, and it has been found that an ideal length for an antisense molecule is from 13 to 30 nucleotides. The researchers felt that they could prevent the expression of a disease-causing gene by synthesizing a complimentary antisense oligonucleotide that would bind to its messenger RNA transcript. Another approach (developed later) involves preparing antisense that would bind directly to the gene sequence on the DNA molecule.

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