Interferon-alpha enhances the sensitivity of human osteosarcoma cells to etoposide

The purpose of these studies was to determine whether interferon-alpha (IFN -alpha) could enhance the sensitivity of human osteosarcoma cells to the cy totoxic actions of etoposide (VP-16), Cytostasis was determined using a [H- 3]thymidine incorporation assay, whereas cytotoxicity was quantified by a c olony-formation assay. Low concentrations (0.1-5 U/ml) of IFN-alpha enhance d the cytostatic activity of VP-16 against MG-63, SAOS-2, and TE-85 osteosa rcoma cells. The cytostatic activity of 1 mu M VP-16 rose from 11% to 64%, 9% to 31%, and 10% to 71%, respectively, in the three cell lines when IFN-a lpha was present. Survival fraction was also decreased when the osteosarcom a cells were treated with VP-16 + IFN-alpha as compared to either agent alo ne. The interaction between these two agents was determined to be synergist ic rather than additive by interaction index analysis. Similar effects on c ytostasis and cytotoxicity were observed when IFN-alpha was combined with A driamycin but not cisplatin, actinomycin D, vinblastine, or amsacrine, VP-1 6 uptake was enhanced 12-fold in the presence of IFN-alpha, but this did no t appear to translate into an increase in topoisomerase-II (topo-II)-DNA co mplex formation as quantified by the sodium dodecyl sulfate-KCl precipitati on assay. We also could not detect alterations in topo-II expression, topo- II protein production, or cell cycle kinetics that have been shown to corre late with increased VP-16 cell sensitivity. Therefore, at this time the mec hanism of enhanced cell sensitivity to the combination treatment remains un clear.