title: Application of mRNA regulatory regions to improve tumor specificity of transgene expression.
abstract: Efficiency and specificity are two key attributes of anti-cancer drugs including genetic therapeutic agents. We suggest a way to improve specificity of gene therapy drugs based on the ability of 3'-untranslated regions (UTR) of some mRNAs selectively stabilize transcripts only during cell division. The mRNAs of genes encoding DNA methyltransferase I (DNMT1) and topoisomerase IIα (TOP2A) are among such transcripts. When inserted into genetic constructs designed to produce therapeutic protein in tumor cells, such 3'-UTR would lead to diminished effect of therapeutic protein on normal cells, which are characterized by low or absent proliferative activity. However, when included in gene expression cassette, these 3'-UTR might result in decreased transgene expression, thus, overweighting the advantage of increased specificity of expression. We showed that DNMT1 and to the lesser extent TOP2A 3'-UTR do not alter significantly therapeutic transgene expression level in tumor cells, thus, confirming the functionality of the proposed approach.
authors: Department of Cancer Gene Therapy, Institute of Gene Biology, Russian Academy of Sciences, Moscow.
authors: M V
authors: MV
authors: Shepelev
authors: E V
authors: EV
authors: Korobko
authors: G P
authors: GP
authors: Georgiev
authors: E D
authors: ED
authors: Sverdlov
authors: I V
authors: IV
authors: Korobko
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000951:Antigens, Neoplasm / Q000235:genetics; D002478:Cells, Cultured; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D015316:Genetic Therapy; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger / Q000235:genetics*; D019076:Transgenes / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D020413:3' Untranslated Regions; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human