Brain Cancer Treatment Shows Promising Result

In trials on mice, tumors reduced by 60%

Richard Saltus, Boston Globe 30dec00

Boston -- Scientists have successfully tested a new method of delivering a promising cancer-fighting substance, endostatin, directly to aggressive brain tumors in mice, shrinking the cancers by over 60 percent.

The feat is a step toward what scientists hope could be a new way of attacking the most vicious brain tumors, called malignant gliomas, which kill patients in an average of 12 to 18 months.

The researchers at Brigham and Women's Hospital inserted endostatin- producing cells into tiny plastic beads, and when the beads were injected into the tumors, they released a continuous dose of endostatin that attacked the tumors' blood supply.

The tumors were not in the animals' brains, but they were brain tumors transplanted under the rodents' skin.

The report in the current issue of Nature Biotechnology is paired with a paper from Norwegian scientists who got a similar system to work for four months, and did inject the endostatin-secreting cells into tumors in rats' brains.

Dr. Judah Folkman, a Harvard and Children's Hospital surgeon who pioneered the field of anti-angiogenesis -- starving tumors by choking off their blood supply -- said the papers represent a "proof of principle" of a novel way of delivering endostatin. He was not involved in the research.

"The nice thing is they didn't report any side effects, and they got very good tumor suppression," said Folkman, in whose laboratory endostatin and other angiogenesis-inhibiting compounds have been discovered in recent years.

Found naturally in the body, endostatin is being developed commercially as a cancer drug and has been tested for over a year. The drug has been taken orally, but has not been used in brain tumor patients.

In the reports, the scientists encapsulated endostatin-producing cells inside barely visible beads of a substance called alginate, made from seaweed. This was to protect the cells from destruction by the immune system of the mice. The beads allowed endostatin to flow out, but wouldn't admit immune molecules from the host's bloodstream.

The Brigham researchers reported that 21 days after they injected the endostatin cells, the tumors shrank by 62 percent and had sharply lower numbers of blood vessels feeding them. Endostatin prevents new vessels from forming to nourish growing tumors.

"We felt endostatin would be a great molecule" to deliver directly to tumors, said Dr. Peter Black, neurosurgeon-in-chief at Children's Hospital and Brigham, "because it is not a toxic agent as far as we can tell and doesn't affect normal tissues. We felt this would be a good way to bathe the tissue around the tumor and stop new blood vessels from forming."

Black said the next step would be to test the system in other animals to make sure it "doesn't irritate the brain," and the researchers also will test it on tumors actually inside the brains of animals.

He couldn't predict when the method might be ready for trials in human patients.

Local endostatin treatment of gliomas administered by microencapsulated producer cells

Nature Biotech Jan01 V.19, N.1

Tracy-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, Martinsried, 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: Tracy-Ann.Read@PKI.UIB.NO

ABSTRACT

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