ENDOGENOUS TUMOR-NECROSIS-FACTOR ENHANCES TOPOISOMERASE-II INHIBITORSACTIVITY IN HUMAN OVARIAN-CANCER CELL-LINES

In this study, we demonstrated that tumor necrosis factor (TNF), secre ted endogenously by four human ovarian cancer cell lines (A2774, IGROV -1, OVCAR-8, SW626), is biologically active against L929 cells and its activity is specifically inhibited by anti-TNF antibodies. Its endoge nous production is increased by treatment for 24 h with phorbol myrist ate acetate (PMA)/ionomycin (Iono). All cell lines express TNF high-af finity receptors and release only 60-kdalton soluble TNF receptor, bot h spontaneously and after stimulation with PMA/Iono. TNF endogenously secreted by human ovarian cancer cell lines is very efficient in poten tiating the activity-of DNA topoisomerase II inhibitors (doxorubicin, mitoxantrone, VP16). The activity of vinblastine and bleomycin is not potentiated and, more interestingly, cisplatin's activity is inhibited . In 24-h PMA/Iono-stimulated A2774 cells, mitoxantrone specifically g enerated more cleavable complexes than in unstimulated cells. This res ult could provide an important tool in the therapy of human ovarian ca ncer secreting TNF protein, previously considered as a negative progno stic factor.