Endogenous tumor necrosis factor enhances topoisomerase II inhibitors activity in human ovarian cancer cell lines.

In this study, we demonstrated that tumor necrosis factor (TNF), secreted 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 endogenous production is increased by treatment for 24 h with phorbol myristate acetate (PMA)/ Ionomycin (Iono). All cell lines express TNF high-affinity receptors and release only 60-kdalton soluble TNF receptor, both spontaneously and after stimulation with PMA/Iono. TNF endogenously secreted by human ovarian cancer cell lines is very efficient in potentiating 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 generated more cleavable complexes than in unstimulated cells. This result could provide an important tool in the therapy of human ovarian cancer secreting TNF protein, previously considered as a negative prognostic factor.