Antisense nucleic acids targeted to the thymidylate synthase (TS) mRNA translation start site stimulate TS gene transcription

Thymidylate synthase (TS) is a key enzyme in the synthesis of DNA and a target for cancer chemotherapeutic agents. Antisense TS nucleic acids may be useful in enhancing anticancer drug effectiveness. MCF-7 and HeLa cells were transfected with vectors expressing antisense TS RNA or with antisense oligodeoxynucleotides (AS-ODNs) to different TS mRNA regions. Antisense RNAs were targeted to 30 bases of the TS mRNA including part of the stem loop at the translation start site and to 30 bases spanning the exon1/exon2 boundary. AS-ODNs were targeted to the translation start site and the translation stop site. Antisense nucleic acids complementary to the translation start site (and not the exon1/exon2 boundary or translation stop site) significantly enhanced constitutive TS gene transcription. Therefore, TS mRNA sequences appear to be involved in a novel pathway controlling TS gene transcription. Induced transcription could hinder antisense-based attempts to inhibit TS and must be considered when designing such strategies. (C) 1998 Academic Press.