Local endostatin treatment of gliomas administered by microencapsulated producer cells.
We describe a technique for the treatment of malignant brain tumors based on local delivery of the anti-angiogenic protein endostatin from genetically engineered cells encapsulated in ultrapure sodium alginate. Alginate consists of L-guluronic and D-mannuronic acid, which in the presence of divalent cations forms an extended gel network, in which cells reside and remain immunoisolated, when implanted into the rat brain. Here, we show that endostatin-transfected cells encapsulated in alginate maintain endostatin secretion for at least four months after intracerebral implantation in rats. During the implantation period 70% of the encapsulated cells remained viable, as opposed to 85% in in vitro-cultured capsules. Rats that received transplants of BT4C glioma cells, together with endostatin-producing capsules (0.2 microg/ml per capsule), survived 84% longer than the controls. The endostatin released from the capsules led to an induction of apoptosis, hypoxia, and large necrotic avascular areas within 77% of the treated tumors, whereas all the controls were negative. The encapsulation technique may be used for many different cell lines engineered to potentially interfere with the complex microenvironment in which tumor and normal cells reside. The present work may thus provide the basis for new therapeutic approaches toward brain tumors.
Read
T A
TA
Department of Anatomy and Cell Biology, University of Bergen, Norway. Tracy-Ann.Read@PKI.UIB.NO
Sorensen
D R
DR
Mahesparan
R
R
Enger
P O
PO
Timpl
R
R
Olsen
B R
BR
Hjelstuen
M H
MH
Haraldseth
O
O
Bjerkvig
R
R
D000464:Alginates; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D017209:Apoptosis; D001672:Biocompatible Materials; D001932:Brain Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D002214:Capsules; D015687:Cell Hypoxia; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D017690:Cell Transplantation; D003094:Collagen / Q000235:genetics / Q000627:therapeutic use* / Q000633:toxicity; D043169:Endostatins; D005910:Glioma / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D020723:Glucuronic Acid; D006603:Hexuronic Acids; D006801:Humans; D008279:Magnetic Resonance Imaging; D010446:Peptide Fragments / Q000235:genetics / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D014162:Transfection; D014183:Transplantation, Heterologous
D000464:Alginates; D020533:Angiogenesis Inhibitors; D001672:Biocompatible Materials; D002214:Capsules; D043169:Endostatins; D006603:Hexuronic Acids; D010446:Peptide Fragments; D020723:Glucuronic Acid; D003094:Collagen