STIMULATORY EFFECTS OF EGF AND TGF-ALPHA ON INVASIVE ACTIVITY AND 5'-DEOXY-5-FLUOROURIDINE SENSITIVITY IN UTERINE CERVICAL-CARCINOMA SKG-IIIB CELLS

We investigated the effects of epidermal growth factor (EGF) and trans forming growth factor(TGF)-alpha On migration, invasion and matrix met alloproteinase (MMP) expression of uterine cervical-carcinoma SKG-IIIb cells, and whether these growth factors affect pyrimidine-nucleoside- phosphorylase(PyNPase) activity and 5'-deoxy-5-fluorouridine(5'-dFUrd) sensitivity of tumor cells. Tumor-cell migration along a gradient of substratum-bound fibronectin and invasion into reconstituted basement membrane were stimulated by 0.1 to 100 ng/ml of EGF and TGF-alpha in a concentration-dependent manner. The zymography of tumor-conditioned m edium showed that the treatment of tumor cells with EGF and TGF-alpha resulted in an increase of the 92-kDa type-IV collagenase (MMP-9), whi ch was confirmed by immunoblot analysis. These growth factors also up- regulated the expression of PyNPase activity of tumor cells and conseq uently enhanced the anti-proliferative action of 5'-dFUrd, a cytostati c that is biotransformed to 5-fluorouracil (5-FUra) by PyNPase. Howeve r, EGF and TGF-alpha did not have significant effects on the 5-FUra se nsitivity of tumor cells. These results suggest that EGF and TGF-alpha , tumor environmental factors, simultaneously up-regulate the potentia l of uterine cervical-carcinoma cells to invade extracellular matrices and their PyNPase activity, which are subsequently associated with th e specific action of 5'-dFUrd selectively killing tumor cells of gynec ological origin with high invasive and metastatic potential. (C) 1997 Wiley-liss, Inc.