Inhibition of tumorigenesis by a cytosine-DNA, methyltransferase, antisense oligodeoxynucleotide.
This paper tests the hypothesis that cytosine DNA methyltransferase (DNA MeTase) is a candidate target for anticancer therapy. Several observations have suggested recently that hyperactivation of DNA MeTase plays a critical role in initiation and progression of cancer and that its up-regulation is a component of the Ras oncogenic signaling pathway. We show that a phosphorothioate-modified, antisense oligodeoxynucleotide directed against the DNA MeTase mRNA reduces the level of DNA MeTase mRNA, inhibits DNA MeTase activity, and inhibits anchorage independent growth of Y1 adrenocortical carcinoma cells ex vivo in a dose-dependent 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 adrenocortical-specific gene C21 and its expression in tumors in vivo. These results support the hypothesis that an increase in DNA MeTase activity is critical for tumorigenesis and is reversible by pharmacological inhibition of DNA MeTase.
Ramchandani
S
S
Department of Pharmacology and Therapeutics, McGill University, Montreal, PQ, Canada.
MacLeod
A R
AR
Pinard
M
M
von Hofe
E
E
Szyf
M
M
D000818:Animals; D000970:Antineoplastic Agents; D002478:Cells, Cultured; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors*; D019175:DNA Methylation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000517:prevention & control; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010442:Peptide Chain Initiation, Translational; D014176:Protein Biosynthesis; D013255:Steroid 21-Hydroxylase / Q000235:genetics
D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; D013255:Steroid 21-Hydroxylase; D004248:DNA (Cytosine-5-)-Methyltransferases