Retroviral transfer of CPP32beta gene into malignant gliomas in vitro and in vivo.

Malignant gliomas are highly aggressive neoplasms that are very resistant to current therapeutic approaches, including irradiation, chemotherapy, and immunotherapy. To improve the prognosis, it is absolutely essential to explore novel modalities of treatment. Recently, we have demonstrated that interleukin 1beta-converting enzyme (ICE), a mammalian homologue of the Caenorhabditis elegans cell death gene ced-3, induces apoptotic cell death in malignant glioma cells. To date, ICE and ICE-like proteases (the ICE family), such as Ich-1L, CPP32beta, Mch2alpha, and Mch3alpha, have been shown to mediate apoptosis in some cells. The purpose of this study is to determine whether the ICE gene family functions as a useful tool for the treatment of malignant glioma cells through induction of apoptosis. The transient transfection assays showed that CPP32beta and Mch2alpha genes induced apoptotic cell death in malignant glioma cells more effectively than did the ICE, Ich-1L, and Mch3alpha genes. To improve the efficiency of gene transfer into malignant glioma cells, we constructed the retroviral vectors containing the ICE gene family. The retroviral transfer of CPP32beta or Mch2alpha gene effectively induced apoptosis in malignant glioma cells in vitro. Furthermore, treatment of tumors grown in mice with retrovirus containing CPP32beta significantly inhibited growth of the tumors through induction of apoptosis. The retroviral transfer of CPP32beta or Mch2alpha, therefore, may be a novel and promising approach for the treatment of malignant glioma, an invariably fatal tumor.