IFN-beta inhibition of etoposide resistance acquisition in vitro: studies using a human glioblastoma cell line

The inhibition by IFN-beta of acquired resistance to the epipodophillotoxin etoposide was studied using a human glioblastoma cell line, T98G. T98G cells were exposed to either etoposide alone or both etoposide and IFN-beta, and after subculture, the same two series of drug exposure were repeated. Degree of level of resistance was tested by the response of the cells to etoposide and changes in their DNA histograms. Furthermore, topoisomerase II in each set of cells was subjected to fluorescence staining with monoclonal anti-topoisomerase II antibody, and the amount of fluorescence was measured by flow cytometry. Secondary etoposide exposure showed less cytotoxicity when the first exposure was to etoposide alone. In contrast, the cytotoxicity was almost the same as that after the first exposure when IFN-beta was added. Resistance to etoposide may result from qualitative or quantitative alterations in the target enzyme, topoisomerase II. The present results show that resistant cells have less topoisomerase II than sensitive cells, suggesting that IFN-beta inhibits the acquisition of resistance to etoposide by suppressing the alteration in topoisomerase II. The inhibition of acquired resistance to etoposide by IFN-beta suggests that continuous and repeated chemotherapy for glioblastoma and other malignant tumors may be clinically advantageous.