Human
interferon-beta (IFN-beta) is known to exhibit pleiotropic
biological activities including antitumor effects. On the other hand,
temozolomide (TMZ), an oral bioavailable
alkylating agent with excellent tolerability, has demonstrated efficacy and has become a key therapeutic agent in patients with
malignant gliomas; however, its survival benefit remains unsatisfactory. More recent studies have indicated that there might be favorable therapeutic interactions between IFN-beta and TMZ, although the therapeutic advantages of such a combination have not yet been fully explored. The main aim of the present study was to determine whether an antitumor effect could be potentiated by a combination of IFN-beta and TMZ. The antitumor effect of and cell sensitivity to IFN-beta and TMZ and the synergistic potential of IFN-beta and TMZ in combination were evaluated in six
malignant glioma cell lines. Correlations among the MGMT methylation status, quantitative level of MGMT
mRNA, MGMT
protein expression and the antitumor effect of these agents were also evaluated, since one of the most prominent resistance mechanisms to TMZ involves the DNA repair
protein MGMT. The cell growth inhibitory effects of IFN-beta and TMZ on all tumor cell lines were observed in a dose-dependent manner, and the human
malignant glioma-derived cell lines differed in their sensitivity to TMZ. The MGMT status, including promoter hypermethylation, quantitative
mRNA expression and
protein expression, was strongly correlated with TMZ sensitivity. A synergistic cell growth inhibitory effect and down-regulated MGMT
mRNA levels were significantly observed when a clinically achievable CNS dose of IFN-beta was combined with TMZ, as compared to treatment with IFN-beta or TMZ alone in TMZ-resistant T98G cells. Furthermore, significant amounts of endogenous IFN-beta
protein were detected in TMZ-treated T98G cells by ELISA. These results suggest that the clinical therapeutic efficacy of TMZ might be improved by a combination with IFN-beta in
malignant gliomas unmethylated at the MGMT gene. The data provide an experimental basis for future strategies in TMZ
chemotherapy, although further studies are needed to determine the detailed role of combined IFN-beta and TMZ
chemotherapy in increasing
tumor sensitivity.