GROWTH Inhibition of Gastrointestinal Cancers with Antisense Oligonucleotides to Oncogenes in vitro and in vivo.

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In this study, we examined if antisense oligonucleotides to oncogenes can suppress growth of gastrointestinal cancers in vitro and in vivo. Phosphorothioate-modified antisense oligonucleotides to the c-myc and bcl-2 oncogenes depressed growth of MKN-45 cells, a gastric cancer cell line overexpressing both onccogenes, in a dose dependent manner at concentrations of 0.1-10muM in vitor, whereas the complementary sense oligonucleotides had no effect. Antisense oligonucleotide to the Ki-ras oncogene also inhibited growth of DLD-1 cells, a colon cancer cell line carrying a mutated Ki-ras gene. When analyzed by RT-PCR and c-myc flow cytometry, the c-myc antisense oligonucleotide specifically inhibited expression of the c-myc oncogene in mRNA level as well as in protein level. Nick-end labelling method for histological detection of apoptotic cells revealed that the c-myc and the bcl-2 antisense oligonucleotides increased apoptotic MKN-45 cells, suggesting that apoptosis may be involved in their inhibitory effect on MKN-45 cell growth. Further, antisense oligonucleotides to c-myc and Ki-ras suppressed growth of MKN-45 cells and DLD-1 cells subcutaneously transplanted in nude mice, whereas saline and sense oligonucleotides had no effect. These results suggest that antisense oligonucleotides to oncogenes might be further studied as a possible treatment method for gastrointestinal cancers.