Potentiation of antiglioma effect with combined temozolomide and interferon-β

Abstract

Temozolomide (TMZ) is a DNA methylating agent that has shown promising antitumor activity against high grade glioma. Interferon-beta (IFN-beta) is known to have antiproliferative and antiangiogenic activities. The aim of this study was to elucidate whether an antiglioma effect could be potentiated by the combination of TMZ and IFN-beta. In vitro, the combination of these drugs suppressed the proliferative and migratory activities, as well as enhance of the apoptosis and cell cycle (S phase) arrest of U-87 cells more efficiently than TMZ or IFN-beta alone. IFN-beta exerted a potent inhibitory effect on the proliferation of human umbilical vein endothelial cells (HUVEC); however, no additive or synergistic effect was observed with the addition of TMZ. To determine in vivo effect, nude mice bearing intracerebral U-87 xenograft inoculation were treated with intraperitoneal administration of PBS, TMZ (15 mg/kg for 3 days), IFN-beta (2x10(5) IU for 15 days), and a TMZ + IFN-beta combination. The combined treatment (median 62.0+/-8.6 days, P=0.0005) was observed to significantly increase the survival of the animals compared to treatment with PBS (median 30.0+/-2.5 days), TMZ (median 41.0+/-3.5 days) or IFN-beta (mean 36.0+/-2.5 days). These results suggest that antiglioma activity can be enhanced by the combination of TMZ and IFN-beta, providing the possibility for a new strategy development in the management of malignant glioma.