Intraarterial delivery of genetic vectors for the treatment of malignant brain tumors

Background: The transfer of therapeutic genes into malignant brain tumors h as been the subject of intense preclinical and clinical research in recent years, Most approaches have used direct intratumoral placement of a variety of vectors and genes, such as retroviruses or adenoviruses carrying drug-s usceptibility genes, modified replication-competent herpes virus, and sever al vectors carrying tumor suppressor genes such as the p53 gene. However, c linical results have so far been disappointing, mainly due to the limited a bility to effectively distribute the genetic material into the target cell population. Accordingly, alternative delivery approaches into the central n ervous system, e.g., intravascular, are under investigation. Genetic vector s administered intravascularly are unlikely to penetrate the blood-brain ba rrier and transfer a gene into brain or tumor parenchyma, However, intravas cular delivery of vectors may target endothelial cells lining the blood ves sels of the brain. Since endothelial cells participate in a variety of phys iological and pathological processes in the brain, their modulation by gene transfer may be used for a variety of therapeutic purposes. Angiogenically stimulated endothelial cells within tumors replicate rapidly and hence may become targets for retroviral-mediated gene transfer. Objective: To assess the anti-tumor effect of transferring a drug-susceptib ility gene into endothelial cells of the tumor vasculature. Methods: As a model for this approach we delivered concentrated retroviral vectors carrying a drug-susceptibility gene via the internal carotid artery of rats with malignant brain tumors. The safety and efficacy of this appro ach, without and with subsequent treatment with a pro-drug (ganciclovir), w as evaluated Results: No acute or long-term toxicity was observed after intraarterial in fusion of the vector, Treatment with ganciclovir resulted in variable hemor rhagic necrosis of tumors, indicating preferential transduction of the angi ogenically stimulated tumor vasculature, This was accompanied by severe tox icity caused by subarachnoid hemorrhage and intracerebral hemorrhage in vas cular territories shared by the tumor and adjacent brain. Conclusion: The data indicate that endothelial cells can be targeted by int raarterial delivery of retroviral vectors and can be used for devising new gene therapy strategies for the treatment of brain tumors.