SYNERGISTIC ANTIPROLIFERATIVE EFFECTS OF INTERLEUKIN-1-ALPHA AND DOXORUBICIN AGAINST THE HUMAN OVARIAN-CARCINOMA CELL-LINE (NIH-OVCAR-3)

Interleukin-1alpha (IL-1alpha) exerts antiproliferative effects on a h uman ovarian carcinoma cell line, NIH:OVCAR-3, which is resistant to c linically relevant concentrations of doxorubicin (DOX) and other chemo therapeutic agents. This action of IL-1alpha depends on the presence o f type I (80 kDa) receptors, although no quantitative relationship has been established between receptor occupancy and inhibition of cell gr owth. When NIH:OVCAR-3 cells were exposed to IL-1alpha and DOX in comb ination, a mutual potentiation of the antiproliferative effects of the two agents was observed. This synergistic effect was pot due to IL-1 receptor expression up-regulation by DOX, and receptor-dependent inter nalization of the cytokine was also unaffected. The involvement of IL- 1 receptors is supported by the observation that synergism between the two agents was diminished (but not abolished) in the presence of a sp ecific IL-1 receptor antagonist at concentrations blocking more than 7 5% of IL-1alpha binding. DOX was found to significantly increase IL-1a lpha accumulation by NIH: OVCAR-3 cells after long-term (48 hr) exposu re to the cytokine at 37-degrees, which might be due to increased nons pecific fluid phase uptake or to interference with cytokine degradatio n and/or release processes. The potent synergy of IL-1alpha and DOX ag ainst ovarian carcinoma cells in vitro suggests that this drug combina tion may be effective against this disease in the clinic.