ENHANCEMENT BY TOCORETINATE OF EPIDERMAL GROWTH FACTOR-INDUCED DNA-SYNTHESIS IN HUMAN INTESTINAL EPITHELIAL-CELLS

Tocoretinate (TR) is a hybrid compound composed of ol-tocopherol ester ified with retinoic acid. The present study was conducted to clarify w hether or not TR affects DNA synthesis in a human intestinal cell line , FHs 74 Int. In these cells, addition of 10% Serum resulted in an app roximately 10-fold increase in DNA synthesis as assessed by [H-3]thymi dine incorporation. Epidermal growth factor (EGF) augmented DNA synthe sis three- to fourfold. When EGF was added together with insulinlike g rowth factor-I (IGF-I), which had only a small effect by itself, a com bination of these growth factors reproduced the effect of serum. In qu iescent FHs 74 Int cells, TR had no effect on DNA synthesis by itself. However, when quiescent cells were pretreated with TR for 24 hr, DNA synthesis induced by EGF was markedly enhanced. Thus, in TR-pretreated cells, EGF stimulated DNA synthesis to the same extent as 10% serum. The effect of TR was dose-dependent and the maximal effect was obtaine d by 10(-7) M TR. Pretreatment with TR enhanced the effect of EGF on D NA synthesis but did not change the dose-response relationship for EGF -mediated DNA synthesis. All-trans-retinoic acid had similar stimulato ry effect on EGF-induced DNA synthesis. When the medium was changed du ring the treatment with TR, the effect of TR on DNA synthesis was redu ced. In addition, pretreatment with TR resulted in release of immunore active IGF-I into medium. Finally, the effect of TR was attenuated by an addition of antibody against IGF-I. These results indicate that TR enhances DNA synthesis induced by EGF at least partly by causing autoc rine production of IGF-I in FHs 74 Int cells.