The development of highly efficient virus and non-virus vector systems for gene transfer to and gene therapy of brain tumors has advanced to the stage of clinical trials, but has still not successfully addressed some major limiting factors, such as the inability of a single delivery modality or therapeutic transgene to target a maximum number of tumor cells in diffuse or multifocal tumors, such as human glioblastoma, and to confer eradicating cytotoxicity to the whole neoplastic mass. Moreover, the choice of vectors and the route of their administration dramatically affect both the efficiency of tumor transduction and its spatial distribution, as well as the extent of transgene expression within a brain tumor and outside it, in the surrounding tumor cell-infiltrated tissue.Three main routes of vector delivery to experimental brain tumors are reviewed in this paper: stereotactic or direct intratumoral inoculation; intrathecal and intraventricular injection; and intravascular infusion with or without modification of the blood-brain-tumor-barrier. The pros and cons of all these modes of application are discussed in respect to the specific and unique features of tumors in the central nervous system. We conclude that, at the present time, there is no ideal vector or unconditionally efficient application mode, and so the successful approaches to brain tumor gene therapy need to combine different application routes with different vectors and therapeutic genes designed to address the individual features of different tumor types. The intravascular vector delivery route, although at an early stage of development, seems to be the most pervasive and demonstrates the greatest therapeutic potential in animal experiments, but for human use it should be combined either with direct intratumoral vector injections or with CSF vector delivery.
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