Gene expression profiles predicting the response to IFN-β and a combination of temozolomide and IFN-β in malignant gliomas

Temozolomide (TMZ) is an alkylating agent that has yielded significant benefits and is a current standard agent in the treatment of malignant gliomas. However, its survival benefit remains unsatisfactory. Recently, a synergistic antitumor effect between TMZ and interferon-beta (IFN-beta) was reported in malignant glioma cells. The Japan Clinical Oncology Group (JCOG) brain tumor study group has recently began a randomized phase II study to evaluate the clinical effectiveness of combination therapy with TMZ and IFN-beta in glioblastomas. However, it is not sufficient just to evaluate the mechanisms and establish an experimental basis for rational clinical therapy with IFN-beta and TMZ. The precise mechanisms governing the direct effects of IFN-beta and a combination of IFN-beta and TMZ in gliomas are not yet fully understood. To gain insight into the mechanisms of sensitivity/resistance involving IFN-beta and combination therapy with IFN-beta and TMZ, and further to identify new marker(s) that could be used clinically to predict the response to such therapy and new target gene(s) for therapies related to malignant glioma pathogenesis, we evaluated the gene expression profiles of human malignant glioma cell lines employing a high-density oligonucleotide DNA array, GeneChip. We present a list of the most highly upregulated and downreeulated genes which may be involved in conferring a response to IFN-beta and synergistic effect between IFN-beta and TMZ in malignant gliomas. Although the present study has several limitations, our reported candidate genes could represent not only potential molecular markers but also chemotherapy targets for improving the treatment outcome by devising strategies that are able to circumvent primary drug resistance in malignant gliomas.