BETA-GALACTOSIDASE GENE-TRANSFER TO HUMAN-MALIGNANT GLIOMA IN-VIVO USING REPLICATION-DEFICIENT RETROVIRUSES AND ADENOVIRUSES

Both retro- and adenovirus-mediated gene therapy have been suggested a s a novel approach to the treatment of malignant brain tumors, However , little information is available about the gene transfer efficiency i n human malignant glioma in vivo, We compared the feasibility and safe ty of retrovirus- and adenovirus-mediated P-galactosidase gene transfe r in human malignant glioma, beta-Galactosidase gene was transferred t o 10 patients with malignant glioma via a catheter inserted into the t umor, The catheter was left in place until the tumor resection, To max imize gene transfer efficiency, gene transfer vectors (BAG retroviruse s, titer, 6 x 10(5) CFU; and adenoviruses, titer from 3 x 10(8) to 3 x 10(10) PFU) were injected into the tumor via the catheter once a day for three consecutive days, followed by tumor resection 1-2 days later , Tumor was resected in such a way that the catheter was still in plac e inside the tumor, which permitted accurate histological analysis of the transduced tumors, X-Gal staining for beta-galactosidase activity was used to study gene transfer efficiency and distribution of the mar ker gene, beta-Galactosidase gene transfer was well tolerated with bot h vectors, Except for two patients with clear increases in serum adeno virus antibody titers, no adverse tissue responses or systemic complic ations were noticed in any off the patients, Gene transfer was success ful in all patients, Gene transfer efficiency varied between < 0.01 an d 4% with retroviruses and between < 0.01 and 11% with adenoviruses, H owever, the transgene activity was not evenly distributed in the tumor s, Both glioma cells and endothelium in the tumor blood vessels were t ransduced with retro- and adenovirus vectors, In conclusion, the safet y and feasibility of in vivo gene transfer to human malignant glioma w as established with retro- and adenovirus vectors, Adenoviruses were m ore efficient than retroviruses in achieving in vivo gene transfer, Tr ansduction of endothelial cells may have important consequences for th e proposed treatment strategies and selection of treatment genes, The results justify clinical gene therapy trials for malignant glioma.