Intraarterial delivery of genetic vectors for the treatment of malignant brain tumors.
BACKGROUND
The transfer of therapeutic genes into malignant brain tumors has 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-susceptibility genes, modified replication-competent herpes virus, and several vectors carrying tumor suppressor genes such as the p53 gene. However, clinical results have so far been disappointing, mainly due to the limited ability to effectively distribute the genetic material into the target cell population. Accordingly, alternative delivery approaches into the central nervous system, e.g., intravascular, are under investigation. Genetic vectors administered intravascularly are unlikely to penetrate the blood-brain barrier and transfer a gene into brain or tumor parenchyma. However, intravascular delivery of vectors may target endothelial cells lining the blood vessels of the brain. Since endothelial cells participate in a variety of physiological 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-susceptibility 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 approach, without and with subsequent treatment with a pro-drug (ganciclovir), was evaluated.


RESULTS
No acute or long-term toxicity was observed after intraarterial infusion of the vector. Treatment with ganciclovir resulted in variable hemorrhagic necrosis of tumors, indicating preferential transduction of the angiogenically stimulated tumor vasculature. This was accompanied by severe toxicity caused by subarachnoid hemorrhage and intracerebral hemorrhage in vascular territories shared by the tumor and adjacent brain.


CONCLUSIONS
The data indicate that endothelial cells can be targeted by intraarterial delivery of retroviral vectors and can be used for devising new gene therapy strategies for the treatment of brain tumors.
Cohen
Z R
ZR
Department of Neurosurgery, Sheba Medical Center, Tel-Hashomer, Israel.
Duvdevani
R
R
Nass
D
D
Hadani
M
M
Ram
Z
Z
D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000494:pharmacology*; D018316:Gliosarcoma / Q000473:pathology / Q000628:therapy*; D007261:Infusions, Intra-Arterial; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D012190:Retroviridae; D012680:Sensitivity and Specificity; D015996:Survival Rate; D016896:Treatment Outcome