By David N. Leff
Editor's note: Science Scan is a roundup of recently published, biotechnology-relevant research.
A front-page article in the New York Times of May 3, 1998, kited the stock of a small biotech start-up, EntreMed Inc., of Rockville, Md. - from $12.06 to as high as $85 the day after the story hit. The article reported - with exuberant optimism of imminent cancer cures - results of preclinical trials in mice of a natural protein, endostatin, which blocks angiogenesis, the proliferation of blood vessels in budding tumors. The company's stock now trades at $16.50.
EntreMed holds the license to endostatin, discovered by surgeon Judah Folkman - the founding father of anti-angiogenesis - at Harvard-affiliated Boston Children's Hospital. Endostatin has since been subjected to numerous preclinical studies, and does a good job starving incipient cancer cells of their blood-borne oxygen and nutrient growth fixes. (See BioWorld Today, Aug. 12, 2000, p. 1.)
But so far, as an effective anti-angiogenesis agent, endostatin has shown several Achilles' heels. Mainly, with an exceedingly short half-life of seven hours, it's rapidly cleared from the blood. Hence, "The quantity of protein needed for this therapy, the purification procedure for large-scale production, and the attendant cost of these processes suggest that alternative delivery methods may be required for efficient therapeutic use of endostatin."
An article in the January issue of Nature Biotechnology made this point, and reported a strategy around these drawbacks. Its title: "Continuous release of endostatin from microencapsulated engineered cells for tumor therapy." The paper's corresponding author, neuroscientist Rona Carroll, is on the Harvard Medical School faculty, and acquired her experimental endostatin cDNA as a gift from Folkman.
The cancer her team tackled is malignant glioblastoma, a highly aggressive solid brain tumor, with a patient survival prognosis of 12 to 18 months. In in vivo testing, they injected the right flanks of nude mice subcutaneously with nascent human glioma cell lines. Ten days later, the xenografted tumors had reached 290 cubic millimeters in size. Then they treated the animals with systemic injections of a human endostatin cDNA expression vector. This was packaged into transformed baby hamster kidney cells, loaded into alginate coated with poly-L-lysine (to fend off immune tissue rejection), forming microcapsule beads averaging 0.7 millimeters in diameter. Three weeks later, the growth of the glioma tumors was suppressed by 62.2 percent, and their weight reduced by 72.3 percent - compared to control animals.
"This delivery system," the paper pointed out, "may be useful for the treatment of brain tumors, wherein the blood-brain barrier can impede systemic treatment of anti-angiogenic agents, and may also overcome obstacles such as the short half-life of endostatin, repeated administration, high doses and cost."
It concluded: "Additional studies using intracranial tumor models are presently under way to further assess the efficacy of this microencapsulated cell endostatin delivery system."
In fact, cell biologists at Norway's University of Bergen report similar experiments in which they administered the glioma cells and endostatin beads intracranially to rats rather than systemically to mice. Their paper, back-to-back in the January Nature Biotechnology with Carroll's, bears the title: "Local endostatin treatment of gliomas administered by microencapsulated producer cells."
The Norwegian rats survived 84 percent longer than controls, with 70 percent of the microencapsulated endostatin cells still alive after four months.
"They did their experiments differently," Carroll told BioWorld Today, "in that they gave the tumor cells and endostatin treatment at the same time. We let our tumors grow for a week, so they're actually established before we start the cell therapy, which is more like what would happen in a clinical setting.
"We have to do a lot more basic research before we contemplate human trials," she added. "Our thought is that the neurosurgeon, immediately after taking out the bulk of the tumor, places the capsules into the tumor bed, where they would continue to secrete the endostatin."
Finally Found, In The Spinal Cord Of Cats, The Discrete Neurons That Signal Itch, But Not Pain
There was a young belle of old Natchez
Whose garments were always in patches.
When comment arose
On the state of her clothes,
She drawled: "Where Ah itches, Ah scratches."
That Southern lady was not alone in her discomfort.
"Intractable itchiness," neurobiologist Arthur Craig told BioWorld Today, "is a serious clinical problem for several diseases of internal organs, such as the liver and the kidney. It's an untreatable side effect of the spinal use of morphine for pain relief, which is a common epidural analgesic in labor and delivery. There is no treatment for this pruritis," Craig continued. "Itchiness can be caused by exposure to certain chemicals, certain plant cells - notably poison ivy - that can be treated topically with corticosteroids, but there is no systemic or pharmaceutical agent that can act against itchiness."
Craig, a senior staff scientist at the Barrow Neurological Institute of St. Joseph's Hospital and Medical Center in Phoenix, is senior author of a paper in the January 2001 issue of Nature Neuroscience. Its title: "Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch." He studied this itchiness in 33 cats treated through the hairy feline skin by iontophoresis with itch-inducing histamine.
"We identified cells in the central nervous system," Craig explained, "that selectively signal chemicals in the skin that cause a pure itch sensation. This is the first time such specific cells have been found in the CNS. This suggests very clearly that there is a biochemical selectivity to this pathway, which raises the future possibility of identifying some features that might be used as therapeutic targets.
"We have prior evidence," he went on, "indicating that the selective neurons that accompany these itch cells are morphologically distinct, which means they are also biochemically distinct. And by identifying such cells morphologically we may be able to dissect them out singly. Then, using modern molecular biological tools, try to capture some identifying features that might collectively abolish or reduce the activity of these cells."