Here is the entire text of the NYT article (in case the link expires eventually).
(This article is clearly negative for ENMD. Yet, ENMD traded up about $1 for about 15 to 30 minutes or so this morning before people figured things out ...)
March 16, 1999
Progress Reported in Attacking Tumor Blood
Supply
By NICHOLAS WADE
Researchers are reporting new insights into understanding angiogenesis,
the body's process of forming new blood vessels, and how it might be
blocked as a therapy against cancer.
In Tuesday's issue of the Proceedings of the National Academy of Sciences,
one team of biologists says it has isolated a new kind of angiogenesis inhibitor
from human cartilage.
As with other angiogenesis inhibitors, biologists
hope that it can be used in patients to cut off
the blood supply on which tumors depend.
Another group of researchers describes a
revealing discovery about angiostatin, a
powerful angiogenesis inhibitor discovered
recently in the laboratory of Dr. Judah Folkman, the pioneer of the field.
After five years' work, Tammy L. Moser and other biologists at Duke
University have now identified sites on blood vessel cells that are probably the
receptors to which angiostatin binds.
A colleague, Dr. Salvatore Pizzo, said that now that the binding site was
known it might be possible to design a small molecule that would home in on
it as accurately as angiostatin does.
That would improve chances of developing an anti-cancer treatment because
angiostatin itself is very hard to manufacture in active form. The
Bristol-Myers Squibb Company recently halted its work on angiostatin, saying
it doubted enough could be made to support clinical trials.
Angiostatin is hard to make because its protein chain has three or four
cross-linked regions known as kringles, after the Danish cookie of the same
name. The cross links in each kringle do not form as efficiently in the
manufacturing process as they do in human cells.
"I have been skeptical for quite a while that angiostatin could be used as a
drug candidate. Our yields were terrible," Dr. Pizzo said.
Dr. Folkman, who works at Children's Hospital in Boston, said that people
were slowly learning how to make angiostatin but that "if someone could
bypass it and make a small molecule that's effective, that would be a major
step, that would be wonderful." Discovery of the angiostatin binding site by
the Duke University scientists "provides a glimpse that you could do that," he
said.
Another interesting aspect of the Duke biologists' study is that it may explain
how angiostatin works.
The site to which angiostatin binds is a large protein enzyme, known as ATP
synthase, which generates energy for the cell. By closing the enzyme down,
angiostatin may disrupt the energy supply to blood vessels.
ATP synthase, as the enzyme is called, is usually an interior protein and has
not before been found on the outside membrane of a cell.
Dr. Harrison Farber of Boston University, an expert on blood vessels' ability to
survive without much oxygen, said the Duke biologists' finding was surprising
but plausible.
The new angiogenesis inhibitor from human cartilage was found by Marsha
A. Moses of Children's Hospital and colleagues. Dr. Moses said she was
following up an observation made by Dr. Folkman in the 1980's, that when
pieces of raw cartilage were dropped into a chicken embryo, the blood vessels
would move away as if repelled by some factor in the cartilage.
Returning to the pursuit of the factor with new methods, Dr. Moses and her
colleagues discovered a substance in the cartilage of cow shoulder bones that
powerfully inhibited blood-vessel growth. The substance turned out to be a
protein well known in another context. It is called troponin I, and is a subunit
of the protein complex that controls muscle contraction.
The equivalent human protein was then isolated from rib cartilage and was
found also to inhibit angiogenesis.
Dr. Moses' research was financed by Boston Life Sciences, a biotechnology
company, which is testing troponin I's usefulness in treating the spread of
melanoma. The company is conducting animal tests to calculate the best dose
to use in future clinical trials, which will be on head and neck cancer and on
preventing cancer spread in sarcoma patients. Dr. Marc E. Lanser, the
company's chief scientific officer, said that in a standard laboratory test
troponin I proved to be considerably more potent than either angiostatin or
endostatin.
Could troponin I have anything to do with claims about the effectiveness of
shark cartilage for treating cancer? Probably not. If there is any troponin I in
shark cartilage, it would be destroyed by stomach acid, could not in any case
cross the wall of the gut, and even if it did so would not reach any tumors in
meaningful doses, Dr. Folkman said.
Dr. Gerald Soff, an angiogenesis expert at Northwestern University Medical
School, said that troponin I appeared to be a very active agent. "The concept
of angiogenesis inhibitors' suppressing cancer has long ago been validated to
everyone's satisfaction and it's now a matter of a very aggressive race, both
academically and financially, to come up with an effective inhibitor. It may be
troponin I will be one of the candidates," he said.
Dr. Folkman said the new findings might also prove relevant to arthritis
because cartilage is often destroyed by invading blood vessels. " Arthritis
specialists will probably start to ask if troponin is lost or destroyed in some
way before the blood vessels come in," he said.
A curious feature of angiogenesis is the way it is controlled. The generation of
new blood vessels, such as in wound healing or menstruation, is not a casual
matter for the body; the vessels need to be switched on and off with same
precision as blood clotting. Yet instead of having a dedicated set of signals to
close down new blood vessels, the body scavenges pieces from other
systems.
Angiostatin is a part of a larger protein called plasminogen, which plays a vital
role in blood clotting. The angiogenesis inhibitor is generated when certain
enzymes cleave it out of its parent plasminogen molecule.
Similarly endostatin, another angiogenesis inhibitor found in Dr. Folkman's
laboratory, is cleaved out of collagen, the main structural protein of skin.
Troponin I is not generated by cleavage but its angiogenesis effect seems
secondary to its other duties in muscle contraction.
Several angiogenesis inhibitors are being tested as tumor suppressors in
clinical trials, although angiostatin and endostatin are not yet among them. Dr.
Folkman hopes some will prove effective but does not expect any drastic
advance in treatment. He believes physicians will start to use the various
inhibitors in conjunction with conventional treatments like chemotherapy and
radiation.
Dr. Soff noted that many universities and companies were now working in
the field that Dr. Folkman pioneered. "Not taking anything away from Dr.
Folkman," Dr. Soff said, "we should keep an open mind as to where the first
antiangiogenesis compounds will come from."
The particular promise of antiangiogenesis lies in the fact that the blood vessel
cells it targets are normal cells and thus not expected to develop resistance to
agents directed against them. Cancer cells, by contrast, are genetically
unstable and quickly grow immune to chemicals and radiation, which is why
cancer is such an intractable disease.
Copyright 1999 The New York Times Company |
