Selective anti-gene therapy for cancer: principles and prospects.
Oligodeoxynucleotides can act as antisense complements to target sense sequences of natural mRNAs to selectively regulate gene expression by translation arrest. This is a form of interventional gene therapy. Chemically modified analogs that are nuclease-resistant enable this strategy to be utilized in practice. Of the chemically modified backbone analogs of oligodeoxynucleotides we have used the phosphorothioate (PS) analog, in which a non-bridging phosphate oxygen atom is substituted with a sulfur atom. We have shown that these oligodeoxynucleotide analogs inhibit beta-globin expression in cell free systems, and that they are taken up by cells. Specific sequences have been shown to selectively regulate viral and cellular gene expression, for example the bcl-2 oncogene that is found in ca. 90% of lymphomas. However, the PS analog has certain disadvantages, notably reduced hybridization and non-selective inhibition of translation. We have therefore synthesized a series of (PS-PO) co-polymers and characterized their properties. Other related approaches include catalytic ribozymes, and formation of triplexes by direct interaction of oligomers in the major groove of DNA. In general, a chemically modified oligodeoxynucleotide analog can be regarded as a novel form of informational drug.
Cohen
J S
JS
Cancer Pharmacology Department, Georgetown University Medical School, Rockville, MD.
D000818:Animals; D001483:Base Sequence; D002474:Cell-Free System; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy*; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*
D016376:Oligonucleotides, Antisense