SPECIFIC REGULATION OF GENE-EXPRESSION BY ANTISENSE NUCLEIC-ACIDS - ASUMMARY OF METHODOLOGIES AND ASSOCIATED PROBLEMS

Gene therapy based on gene-specific nucleic acids has moved from theor y to a practical possibility in a very short time. The new DNA and RNA therapeutic reagents are intended to stop the growth of cancerous cel ls or the production of viruses. At the practical level, the efficacy of antisense oligomers as therapeutic reagents has been carefully exam ined in various clinical contexts. For the efficient use of antisense nucleic acids as pharmaceutical agents, a complete analysis of their m echanisms of action is necessary. The use of antisense oligomers alway s involves the following problems: basepair specificity, stereoisomer specificity, stability and resistance to nucleases of sense-antisense duplexes, permeability of the cell membrane and targeting of the oligo mer, safety, and the preparation of large amounts of oligomer. Herein, we review the basic concepts and problems associated with the exploit ation of antisense technology. We have identified a new transcription factor triple-helix-binding zinc-finger protein-1 (THZif-1) induced by antisense c-myc RNA in the antisense-transformed HL60 cells. The enco ded protein functions as the repressor of c-myc to achieve the reducti on of the endogenous expression of c-myc gene. Therefore, the introduc tion of THZif-1 gene into HL60 cells in conjunction with antisense c-m yc oligomers may result in the efficient repression of the expression of the c-myc gene, The molecular features of this factor are herein di scussed.