2-5A-Antisense: A Novel Approach to Cancer Therapy

In the past two decades, the identification and cloning of genes responsible for human malignancies has led to the first concerted efforts aimed at controlling cancer by blocking the expression of both oncogenes and genes which suppress the immune system’s response to cancer. Attempts at inhibiting the expression of harmful genes is approached in a selective and versatile manner through the use of antisense nucleic acids (reviewed in refs. 1 – 5). “Antisense” refers to the concept that nucleic acids which are complementary in sequence may anneal by Watson-CIick base pairing in cells and inhibit gene expression. Because mRNA is considered to be in the “sense” orientation, complementary sequence is called antisense. Antisense is highly selective in its mode of action because most genes have at least a stretch of sequence which is unique in nature. Therefore, one can use antisense which will bind with a much higher affinity to the targeted nucleic acid than to any other sequence. This highly selective mode of action makes antisense much more specific than conventional chemotherapeutic agents. Any gene, the sequence of which is known, can be targeted by synthesizing a strand of antisense. Binding of antisense to RNA produces stretches of duplex or double-stranded nucleic acid that can interfere with RNA processing and function at any one of several different levels. Possible mechanisms of antisense action include, but are not limited to, inhibition of transcription through formation of triplex structures with DNA, interference with mRNA splicing and transport to cytoplasm, induction mRNA decay, and inhibition of translation.