Intra-arterial delivery of endostatin gene to brain tumors prolongs survival and alters tumor vessel ultrastructure.
Glioblastoma multiforme (GBM) is an incurable malignant brain tumor, usually fatal within 1 year of diagnosis. Using a syngeneic rat 9L gliosarcoma model, we have developed a novel drug delivery method in which naked plasmid DNA is selectively targeted to brain tumors via intra-arterial injection. Using a plasmid encoding the antiangiogenic endostatin, transgene expression can be detected in tumor cells in vivo, and therapeutic efficacy is observed. Administration of this plasmid resulted in an 80% tumor volume reduction 1 week after treatment and enhanced survival time by up to 47%. Treated tumors exhibited a 40% decrease in the number of tumor vessels; ultrastructural analysis of remaining tumor vessels demonstrated a number of changes including markedly narrowed or collapsed lumens. We conclude that intra-arterial injection of plasmids selectively targets therapeutic genes to CNS neoplasms. This method of gene therapy holds promise for the treatment of these highly malignant brain tumors.
Barnett
F H
FH
Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Scharer-Schuksz
M
M
Wood
M
M
Yu
X
X
Wagner
T E
TE
Friedlander
M
M
D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology; D001932:Brain Neoplasms / Q000401:mortality / Q000628:therapy* / Q000648:ultrastructure; D002199:Capillary Permeability / Q000502:physiology; D043169:Endostatins / Q000008:administration & dosage / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005909:Glioblastoma / Q000401:mortality / Q000628:therapy* / Q000648:ultrastructure; D007150:Immunohistochemistry / Q000379:methods; D007269:Injections, Intra-Arterial; D008297:Male; D008854:Microscopy, Electron / Q000379:methods; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D010957:Plasmids; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016896:Treatment Outcome
D043169:Endostatins