INHIBITION OF TUMORIGENESIS BY A CYTOSINE-DNA, METHYLTRANSFERASE, ANTISENSE OLIGODEOXYNUCLEOTIDE

This paper tests the hypothesis that cytosine DNA methyltransferase (D NA MeTase) is a candidate target for anticancer therapy. Several obser vations have suggested recently that hyperactivation of DNA MeTase pla ys a critical role in initiation and progression of cancer and that it s up-regulation is a component of the Ras oncogenic signaling pathway, We show that a phosphorothioate-modified, antisense oligodeoxynucleot ide directed against the DNA MeTase mRNA reduces the level of DNA MeTa se mRNA, inhibits DNA MeTase activity, and inhibits anchorage independ ent growth of Y1 adrenocortical carcinoma cells ex vivo in a dose-depe ndent manner, Injection of DNA MeTase antisense oligodeoxynucleotides i.p. inhibits the growth of Y1 tumors in syngeneic LAF1 mice, reduces the level of DNA MeTase, and induces demethylation of the adrenocortic al-specific gene C21 and its expression in tumors in vivo, These resul ts support the hypothesis that an increase in DNA MeTase activity is c ritical for tumorigenesis and is reversible by pharmacological inhibit ion of DNA MeTase.