CELL-SURFACE PERTURBATIONS OF THE EPIDERMAL GROWTH-FACTOR AND VASCULAR ENDOTHELIAL GROWTH-FACTOR RECEPTORS BY PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDES

Antisense oligodeoxynucleotides offer potential as therapeutic agents to inhibit gene expression, Recent evidence indicates that oligodeoxyn ucleotides designed to target specific nucleic acid sequences can inte ract nonspecifically with proteins. This report describes the interact ive capabilities of phosphorothioate oligodeoxynucleotides of defined sequence and length with two essential protein tyrosine receptors, flk -1 and epidermal growth factor receptor (EGFR), and their effects on r eceptor signaling in a transfected and tumor cell line, respectively, Phosphorothioate oligodeoxynucleotides bound to the cell surface, as d emonstrated by fluorescence-activated cell-sorter analyses (FAGS), and perturbed receptor activation in the presence and absence of cognate ligands, EGF (EGFR) and vascular endothelial growth factor (flk-1), in phosphorylation assays, Certain phosphorothioate oligodeoxynucleotide s interacted relatively selectively with flk-1 and partially blocked t he binding of specific anti-receptor monoclonal antibodies to target s ites, They stimulated EGFR phosphorylation in the absence of EGF but a ntagonized ligand-mediated activation of EGFR and flk-1. In vivo studi es showed that a nonspecific phosphorothioate oligodeoxynucleotide sup pressed the growth of glioblastoma in a mouse model of tumorigenesis, These results emphasize the capacity of phosphorothioate oligodeoxynuc leotides to interact with cells in a sequence-selective nonantisense m anner, while associating with cellular membrane proteins in ways that can inhibit cellular metabolic activities.