Effects of Sex Steroids and Growth Factors on Invasive Activity and 5′‐Deoxy‐5‐fluorouridine Sensitivity in Ovarian Adenocarcinoma OMC‐3 Cells

Effects of sex steroids (estradiol‐17β, E(2); progesterone, Prog) and growth factors (epidermal growth factor, EGF; transforming growth factor‐α, TGF‐α) on invasive activity and 5′‐deoxy‐5‐fluorouridine (5′‐dFUrd) sensitivity of ovarian adenocarcinoma OMC‐3 cells were investigated. Tumor cell migration along a gradient of substratum‐bound fibronectin and invasion into reconstituted basement membrane were inhibited by 10 μM Prog, but stimulated by 0.1–10 nM EGF and TGF‐α in a concentration‐dependent manner. E(2) did not have any effect on tumor cell migration or invasion. The zymography of tumor conditioned medium showed that the treatment of OMC‐3 cells with EGF and TGF‐α resulted in increases of type IV collagenase, stromelysin and urokinase‐type plasminogen activator (uPA). EGF and TGF‐α up‐regulated thymidine phosphorylase (dThdPase) expression of tumor cells and consequently enhanced the antiproliferative action of 5′‐dFUrd, which is converted to 5‐fluorouracil by dThdPase. E(2) and Prog did not have significant effects on the expression of proteolytic enzymes and dThdPase, or on the 5′‐dFUrd sensitivity of tumor cells. The inhibitory effect of Prog on tumor cell invasion may depend on its inhibitory action on the motility of tumor cells. These results suggest that EGF and TGF‐α simultaneously up‐regulate the potential of ovarian adenocarcinoma cells to invade extracellular matrices and their dThdPase expression, both of which are associated with the specific action of 5′‐dFUrd selectively to kill tumor cells with high invasive and metastatic potential.