Antitumor activity of MG98, an antisense oligodeoxynucleotide targeting DNA methyltransferase-1 (DNMT1) in gastric carcinoma

Abstract

1602

Gastric cancer remains a prevalent and difficult to treat form of cancer in humans. Altered patterns of DNA methylation are common in human tumors, as are elevated levels of the DNA-(cytosine-5)-methyltransferase enzymes DNMT1, DNMT3a and DNMT3b. Hypermethylation of CPG islands and resulting transcriptional inactivation of numerous growth regulator genes have been reported in human gastric cancer cells. Moreover, methylation mediated silencing of RUNX3 has recently been proposed as a causative event in the genesis of gastric cancer (Cell, Vol. 109, 113-124, (2002)) . Here we demonstrated that specific inhibition of one of the DNMT enzymes, the maintenance methyltransferase, DNMT1, in human gastric cancer cells, by the second generation antisense oligodeoxynucleotide (ODN) MG98, reactivates expression multiple methylation silenced tumor suppressor genes. Furthermore, MG98-induced depletion of DNMT1 in AGS, Kato III and MKN74 human gastric cancer cells in vitro resulted in significant growth inhibition concomitant with the re-expression of the silenced tumor suppressor genes p16ink4a and RUNX3. We also demonstrate that treatment of nude mice bearing MKN74 tumor xenografts resulted in tumor growth inhibition in vivo. These preclinical data support the role of DNA methylation in the maintenance of human gastric cancer and suggest that demethylating drugs such as MG98 may have utility in the treatment of human gastric cancer.