ANTISENSE TRANSFORMING GROWTH FACTOR-ALPHA OLIGONUCLEOTIDES INHIBIT AUTOCRINE STIMULATED PROLIFERATION OF A COLON-CARCINOMA CELL-LINE

Many carcinoma cells secrete transforming growth factor alpha (TGFalpha). A 23 base anti-sense oligonucleotide that recognizes the TGFalpha mRNA inhibits both DNA synthesis and the proliferation of the colon carcinoma cell line LIM 1215. The effects of the anti-sense TGFalpha oligonucleotide are reversed by epidermal growth factor (EGF) at 20 ng/ml. When the LIM 1215 cells are grown under serum free conditions, the anti-sense TGFalpha oligonucleotides have their greatest effects at high cell density (2 X 10(5) cells/cm2), indicating that the secreted TGFalpha is acting as an exogenous growth stimulus. In addition, at higher cell densities, the kinase activity of the EGF receptor is activated and the receptor is down-modulated. The cell density dependent activation of the EGF receptor is inhibited by the application of the antisense TGFalpha oligonucleotides.