Adenovirus-Mediated Herpes Simplex Thymidine Kinase Gene Therapy For Brain Tumors
Adenovirus-mediated HSVtk gene therapy has been shown to be eefective for the treatment of malignant glioma when the gene transfer efficiency is high. Adenoviruses are currently the most promising vectors for gene therapy of malignant glioma especially be
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ADENOVIRUS-MEDIATED HERPES SIMPLEX THYMIDINE KINASE GENE THERAPY FOR BRAIN TUMORS Anu-Maaria Sandmair1*,2† Matti Vapalahti2,4, and Seppo Ylä-Herttuala 1 *, 3,4 1
A.I. Virtanen Institute University of Kuopio P.O.B. 1627, FIN-70211 Kuopio Finland 2 Department of Neurosurgery 3 Department of Medicine and 4 Gene Therapy Unit University Hospital of Kuopio P.O.B. 1777, FIN-70110 Kuopio Finland
1. INTRODUCTION Intracranial neoplasms continue to challage physicians and scientists, since the poor prognosis specially of malignant glioma has shown only minor improvements despite all attemps to improve the outcome of these patients. Gene therapy is one of the most interesting novel treatment modalities in attempting to change the survival of malignant glioma patients. While holding the promise for an effective treatment of these patients, the transfer of gene therapy from cell culture to animal models and finally to clinical applications presents a great challenge.
2. MALIGNANT BRAIN TUMORS Intracranial neoplasms are divided into primary tumors derived from the central nervous system (CNS) or other structures in cranial cavity, and secondary or metastatic tumors, which spread to CNS without CNS origin. Classification of brain tumors are *Fax: +358-17-163030, †Fax: +358-17-163030 Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
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based on either origin, histological growth pattern and to a lesser extent on radiological and operative appearance. The most frequent primary brain tumors are neuroglial, i.e., astrocytomas, anablastic astrocytomas, glioblastoma multiforme, oligodendrogliomas and ependymomas (Fuller et al., 1996). Etiology of CNS tumors is largely unknown, and the causes can be multiple: maldevelopment, genetic factors, chromosomal aberrations, trauma, viruses, chemical compounds and immunological dysfunctions. However, it has not been possible to draw any final conclusions regarding any single causative mechanism. The overall prognosis of most benign neoplasms have shown improvements, in which easier diagnosis and reduced surgical morbidity have changed the outlook. On the other hand, malignant tumors, especially glioblastoma multiforme, still have a poor outlook, even though prompt diagnosis, aggressive treatment with combined surgery, radiation and chemotherapy have achived some positive effects.
3. MALIGNANT GLIOMA 3.1. Definition and Classification All gliomas occur from well differentiated to anablastic tumors. The term malignant glioma is usually used for those gliomas which show evidence of histological and
biological malignancy with anablasia, invasiveness, tumor recurrency and metastatic spread. These tumors include glioblastoma, somewhat less aggressive anablastic astrocytoma, malignant oligodendroglioma and malignant ependymoma (Fuller et al., 1996). Gliomas have been classified by several different features, sometimes in a confusing way. The World Health Organization (WHO) classification i
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