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January 2001 Volume 19 Number 1 pp 29 - 34

 

 

Local endostatin treatment of gliomas administered by microencapsulated

producer cells

-Ann Read1, Dag R. Sorensen2, Rupavathana Mahesparan1, Per Ø. Enger1,

Rupert Timpl3, Bjørn R. Olsen4, Mari H.B Hjelstuen5, Olav Haraldseth6 & Rolf

Bjerkvig1

 

1. Department of Anatomy and Cell Biology, University of Bergen, Norway.

2. Department of Comparative Medicine, The National Hospital, University of

Oslo, Norway.

3. Max-Planck-Institut für Biochemie, sried, Germany.

4. Harvard Medical School, Boston, MA, USA.

5. SINTEF Unimed, MR Center, 7565 Trondheim, Norway.

6. Department of Anaesthesia and Medical Imaging, The Norwegian University

of Science and Technology, Trondheim, Norway.

Correspondence should be addressed to T -A Read. e-mail:

-Ann.Read@...

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 g/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.

Keywords: alginate, encapsulation, producer cells, brain tumors Articles

 

January 2001 Volume 19 Number 1 pp 35 - 39

 

 

Continuous release of endostatin from microencapsulated engineered cells for

tumor therapy

Tatsuhiro Joki1, 2, 3, 5, Marcelle Machluf4, 5, Atala4, Jianhong

Zhu1, 2, T. Seyfried1, 2, Ian F. Dunn1, 2, Toshiaki Abe3, Rona S.

Carroll1, 2 & McL. Black1, 2

 

1. Brain Tumor Laboratory, Department of Neurosurgery, Department of

Surgery, Brigham Women's Hospital, Harvard Medical School, Boston, MA 02115.

2. Children's Hospital, Harvard Medical School, Boston, MA 02115.

3. Department of Neurosurgery, Jikei University School of Medicine, Tokyo,

Japan.

4. Department of Urology, The Children's Hospital, Harvard Medical School,

Boston, MA 02115.

5. These authors contributed equally to this work.

Correspondence should be addressed to R S Carroll. e-mail:

rcarroll@...

Research studies suggest that tumor-related angiogenesis contributes to the

phenotype of malignant gliomas. We assessed the effect of local delivery of

the angiogenesis inhibitor endostatin on human glioma cell line (U-87MG)

xenografts. Baby hamster kidney (BHK) cells were stably transfected with a

human endostatin (hES) expression vector and were encapsulated in

alginate-poly L-lysine (PLL) microcapsules for long-term delivery of hES.

The release of biologically active endostatin was confirmed using assays of

bovine capillary endothelial (BCE) proliferation and of tube formation.

Human endostatin released from the microcapsules brought about a 67.2%

inhibition of BCE proliferation. Furthermore, secreted hES was able to

inhibit tube formation in KDR/PAE cells (porcine aortic endothelial cells

stably transfected with KDR, a tyrosine kinase) treated with conditioned

U-87MG medium. A single local injection of encapsulated endostatin-secreting

cells in a nude mouse model resulted in a 72.3% reduction in subcutaneous

U87 xenografts' weight 21 days post treatment. This inhibition was achieved

by only 150.8 ng/ml human endostatin secreted from 2 105 encapsulated

cells. Encapsulated endostatin-secreting cells are effective for the

treatment of human glioblastoma xenografts. Continuous local delivery of

endostatin may offer an effective therapeutic approach to the treatment of a

variety of tumor types.

Keywords: Endostatin, encapsulation, angiogenesis, glioma