Opioid growth factor tonically inhibits human colon cancer cell proliferation in tissue culture.

Native opioid peptides serve as growth factors in a number of normal and neoplastic cells and tissues, including the prevention and delayed growth of human colon cancer xenografts in nude mice. This study examined the hypothesis that opioids exert a direct inhibitory influence on tumor cell growth by the use of a tissue culture model. The naturally occurring pentapeptide [Met5]enkephalin depressed growth of HT-29 human colon cancer cells from 17 to 41% at 12-72 h after administration of 10(-6)M concentration; consistent with previously defined nomenclature, this peptide was termed opioid growth factor (OGF). OGF action exhibited a dose-response relationship, was reversible and not cytotoxic, and was opioid receptor mediated. Growth inhibition by OGF was not dependent on serum, and was noted in the two other human colon cancer cell lines examined WiDr and COLO 205. This peptide continually repressed growth because an increase in cell number was noted when cells were exposed to the potent opioid antagonist naltrexone or an antibody to OGF. Both OGF and its receptor, zeta (zeta), were found in colon cancer cells by immunocytochemistry, and receptor binding assays revealed a nuclear-associated receptor with a dissociation constant of 8.9 nM and a maximum binding capacity of 43 fmol/mg of protein. OGF was produced and secreted by the tumor cells. These results lead to the suggestion that OGF has a direct, tonic, inhibitory action on the growth of human colon cancer cells and contribute to our understanding of the mechanisms underlying the marked antitumor effect of this peptide in nude mice inoculated with human colon cancer cells.