ENDOTHELIAL CELL-BASED CYTOKINE GENE DELIVERY INHIBITS 9L GLIOMA GROWTH IN-VIVO

Malignant brain neoplasms present great therapeutic challenges due to their extremely aggressive behavior and relative isolation by the bloo d-brain and blood-tumor barriers. Endothelial cells may be versatile p latforms for delivering genes to solid tumors by virtue of their locat ion at blood-tissue interfaces and their proliferation in response to endothelial mitogens produced by tumors. Immortalized rat brain endoth elial cells that express the E. coli lacZ reporter gene and the gene f or murine interleukin-2 (RBEZ-IL2) were co-inoculated with 9L. glioma cells to Fisher rats to examine the effects of endothelial cell-based cytokine delivery on glioma growth in vivo. 9L glioma growth was not a ffected by the implantation of control RBEZ cells. The growth of subcu taneous and intracranial 9L gliomas was significantly inhibited by RBE Z-IL2 cells (P <0.005 and P <0.001, respectively) when compared to con trol transfected RBEZ cells. Rats receiving intracranial 9L glioma cel ls with RBEZ-IL2 cells showed increased survival (P <0.001). Histologi c and immunohistologic analysis showed enhanced activation of microgli a/macrophages and CD8-positive T lymphocytes and/or natural killer cel ls within brain at sites of 9L inoculation with RBEZ-IL2 cells. This r eport establishes that immortalized endothelial cells can be used for cytokine gene delivery and to activate anti-tumor host responses to ex perimental gliomas within the central nervous system.