[Prospects for antisense therapy].

Abstract

Inability to distinguish between normal and diseased cells by chemotherapeutic agents causes systemic toxic effects. This problem may be solved by the direct genetic approach using antisense oligodeoxynucleotide (AS ODN) based on the specificity of Watson-Crick base pair formation, if an appropriate disease-specific target can be identified. Since the pioneering works by Zamecnik and Stephenson to inhibit gene expression using AS ODN, recent progress in cloning of pathogenic genes and technical advance in the synthesis of ODN analogues have spurred a research effort dedicated to the development of AS therapy for cancer and viral disease. Chemically-modified ODNs such as phosphorothioate analogues, which are nuclease resistant and considered to be suitable for clinical use, can effectively inhibit the expression of activated oncogenes or the viral replication and lead to the growth suppression of cancer cells and viral genomes in vitro and in experiments using animal models as well. Phase I clinical trials, designed to evaluate the toxicity of these compounds in leukemia or AIDS patients, have already commenced. In these trials, which are now in its infancy, a considerable number of problems will be encountered. However, these hurdles may not be insurmountable.