Genetic regulation and therapeutic modulation of apoptosis in human malignant glioma

The recognition of susceptibility to apoptosis as a major factor in tumorigenesis and tumor response to therapy has significantly changed current concepts of the formation of malignant brain tumors and of the basis of their striking resistance to current approaches of therapy. Loss of wild-type p53 activity was the first instance of a defect in the molecular machinery regulating susceptibility to apoptosis that was linked to the progression of gliomas and possibly their resistance to therapy. Further, expression of the antiapoptotic bcl-2 protein is likely to play a role in the failure of malignant gliomas to respond to radiotherapy and chemotherapy. The role of bcl-2 in the tumorigenesis and malignant progression of astrocytic tumors remains controversial. Targeting the CD95 pathway, a powerful endogenous system to regulate cell survival via induction of apoptosis, is a promising novel approach of immunotherapy for malignant gliomas.