It is estimated that cancer affects three out of four families in the United States alone the disease and its treatments cause substantial mortality and morbidity, prompting intense interest in cancer prevention. Most available treatments for cancers are non-specific; meaning that they target all rapidly growing cells, both normal and cancerous. Consequences of these treatments include side effects towards the normal cells. In addition, cancer is a genetically unstable disease. Cancer cells can develop drug resistance through repeated rounds of mutation and selection. This may render a particular non-specific chemotherapeutic treatment ineffective so that new drugs must be administered in its place. To remedy this occurrence, current research is focusing on the genetic level to terminate the disease and to avoid the damaging side effects and development of drug resistance. One avenue of research focuses on antisense oligonucleotide to target the oncogenes, or cancer causing genes, in a specific fashion to completely inhibit the expression of the oncogenes.
Information necessary to produce proteins in cells is contained in genes. In humans it is contained in the human genome and its collection of more than 100,000 genes. Genes are made up of DNA. The DNA molecule is a “double helix”. They are made up of Adenine, Thymidine, Guanine and Cytosine and are bound by hydrogen to complementary nucleotides on the other strand. RNA is the DNA intermediary and carries the information necessary for the cell to produce its specific protein. During the transferring on information the DNA strand partly uncoils. The “sense” strand separates from the “antisense strand.” Because RNA is translated by the cell it is called the “sense strand.” The hybridization of an antisense strand to mRNA can interfere with its translation to protein
. Antisense oligonucleotide are polymers of nucleic acids, which can vary from 12-25 base pairs in length, and which are sequence specific and bind to the target mRNA or DNA through complementary hydrogen bonding. Antisense theory proposes that oligonucleotide, or oligos, recognize specific sequences of mRNA or DNA and bind to them, thus preventing translation or transcription of a gene. Through the binding of an oligo to an mRNA that translates an essential protein for cancer growth, the action of the protein is terminated because the product, an oncoprotein, is never formed
The main advantage of antisense is it offers specificity and point of attack.
Traditional drugs are less effective because they are not as specific and only work when the disease causing protein has already been produced. Whereas, antisense drugs are complementary strands of Mrna and bind to specific nucleotides in its Mrna to inhibit production of a disease causing protein. They can bind to multiple areas whereas traditional drugs can only bind at two points of interaction.
Another advantage of antisense is that it is less complex, than traditional drugs that target proteins. Proteins are complex molecules whose structure is hard to predict, antisense compound are designed to bind to Mrna whose structures are easy to understand.
Experimental results seem to support the antisense theory model. If an antisense oligonucleotide does indeed act in a sequence specific, antisense manner to target a gene that is over expressed in cancer or leukemia cells, gene expression can be inhibited and cell growth