OLIGONUCLEOTIDES AS MODULATORS OF CANCER GENE-EXPRESSION

The delineation of gene function has always been an intensive subject of investigations. Recent advances in the synthesis and chemistry of o ligonucleotides have now made these molecules important tools to study and identify gene function and regulation. Modulation of gene express ion using oligonucleotides has been targeted at different levels of th e cellular machinery. Tripler forming oligonucleotides, as well as pep tide nucleic acids, have been used to inhibit gene expression at the l evel of transcription; after binding of these specific oligonucleotide s, conformational change of the DNA's helical structure prevents any f urther DNA/protein interactions necessary for efficient transcription. Gene regulation can also be achieved by targeting the translation of mRNAs. Antisense oligonucleotides have been used to down-regulate mRNA expression by annealing to specific and determined region of an mRNA, thus inhibiting its translation by the cellular machinery. The exact mechanism of this type of inhibition is still under intense investigat ion and is thought to be related to the activation of RNase H, a ribon uclease that is widely available that can cleave the RNA/DNA duplex, t hus making it inactive. Another well-characterized means of interferin g with the translation of mRNAs is the use of ribozymes. Ribozymes are small catalytic RNAs that possess both site specificity and cleavage capability for an mRNA substrate, inhibiting any further protein forma tion. This review describes how these different oligonucleotides can b e used to define gene function and discusses in detail their chemical structure, mechanism of action, advantages and disadvantages, and thei r applications. (C) 1997 Elsevier Science Inc.