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Retroviral transfer of CPP32beta gene into malignant gliomas in vitro and in vivo
1Department of Neurosurgery and Brain Tumor and Neuro-Oncology Center, The Cleveland Clinic Foundation, Ohio 44195, USA. kondos@cesmtp.ccf.org
Abstract:
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.
Insights
Novel gene therapy using the ICE gene family, specifically CPP32beta and Mch2alpha, effectively induces apoptosis and inhibits malignant glioma tumor growth in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Malignant gliomas are aggressive brain tumors with poor prognosis.
- Current treatments like radiation and chemotherapy show limited efficacy.
- Novel therapeutic strategies are crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the potential of the interleukin 1beta-converting enzyme (ICE) gene family for treating malignant gliomas.
- To determine if specific ICE family members can induce apoptosis in glioma cells.
Main Methods:
- Transient transfection assays to evaluate ICE gene family members' apoptotic potential.
- Construction of retroviral vectors for efficient gene transfer.
- In vitro and in vivo studies using malignant glioma cells and tumors in mice.
Main Results:
- CPP32beta and Mch2alpha genes induced apoptosis in malignant glioma cells more effectively than other ICE family members.
- Retroviral transfer of CPP32beta or Mch2alpha successfully induced apoptosis in vitro.
- Retroviral CPP32beta significantly inhibited tumor growth in mice by inducing apoptosis.
Conclusions:
- The ICE gene family, particularly CPP32beta and Mch2alpha, shows promise for inducing apoptosis in malignant gliomas.
- Retroviral gene therapy with CPP32beta or Mch2alpha represents a novel and potentially effective treatment strategy for malignant gliomas.