gms | German Medical Science

Objective: Temozolomide (TMZ) is a well-tolerated, orally bioactive alkylating agent, which forms cross-links between adjacent strands of DNA, leading to cell death. The DNA repair protein, O⁶-methyguanine-DNA methyltransferase (MGMT) plays an important role in cellular resistant to alkylating agents, and it was reported that methylation of the MGMT promoter in gliomas is a useful predictor of the responsiveness to TMZ. On the other hand, Type I interferon (IFN), as a drug sensitizer, has been widely used in combination with other antitumor agents such as nitrosoureas. In our previous experiments (Cancer Res 2005;65:7573-9), we found that IFN-β sensitized TMZ-resistant glioma cells with the unmethylated MGMT promoter. For the mechanism of action, oligonucleotide microarray, RNAi experiments and ChIP assay revealed that sensitizing effect of IFN-β was possibly due to attenuation of MGMT expression via induction of TP53. Based on these results, the aim of this study is further to explore the synergistic effect of IFN-β and TMZ on nude mice with subcutaneously (s.c.) transplanted human glioma.

Methods: Mice were randomized to separate into six groups (five to six animals per group) and treated when s.c. tumors had reached a volume of between 200 and 400 mm³. IFN-β (2x10⁵ IU per animal) was given i.p. 6 h before i.p. injection of TMZ (50 or 100 mg/kg). Control mice, or mice receiving IFN-β or TMZ alone, also received the corresponding vehicle. Treatments were repeated at 24-hr intervals for a total of five doses.

Results: IFN-β alone did not decrease the tumor growth significantly. TMZ (100 mg/kg) alone suppressed the tumor growth, but did increase the associated body weight loss. In contrast, a combination of IFN-β and 50-mg/kg dose of TMZ decreased the tumor growth very significantly, and complete regression was observed in one of five animals (20%).

Conclusions: The results suggest that prior administration of IFN-β can lead to an increase in the therapeutic index of TMZ.