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Comments:
Commonly available drugs can generate angiostatin INTERNALLY by cleaving the abundant plasminogen protein. No recombinant techniques needed.
---Forwarded article----------------
Cancer victim makes remarkable comeback
By John Crewdson
Her startling recovery might be a fluke, a chance accident, an
inexplicable remission of an often-deadly cancer. Then again, the
15-year-old girl from neighboring Tampa might prove to be the first
patient ever treated successfully with a potential new therapy that
has captured the attention of the medical community and the
non-scientific world alike.
No matter how dramatic, scientists agree that an apparent treatment
success in a single patient can never prove anything. But while
researchers struggle to sort out the complexities of the Florida case,
some things are certain.
Five years ago, when she was diagnosed with bone cancer at the age of
10, doctors were ready to take off the girl's left leg and half of her
pelvis. A year ago, physicians expected that she would be dead within
a few months. Last month she was jogging happily beneath the warm
Florida sun, her astonished doctors reporting that their patient had
"resumed all normal activities."
The girl's physician, Dr. Hans-Christoph Rossbach, a pediatric
oncologist at All Children's Hospital here, declined to identify the
girl, citing medical confidentiality and the uncertainties that still
surround her remission. But in a recent interview at his office,
Rossbach provided general details of the harrowing ordeal experienced
by a patient "who has given us a lot of headaches, and a lot of
surprises."
The girl's first cancer, a bone cancer known as Ewing's sarcoma,
disappeared after standard treatment with chemotherapy and radiation,
according to Rossbach.
A bone marrow transplant vanquished a second cancer, a blood-cell
lymphoma, that followed the first.
The occurrence of two consecutive cancers in the same place was
unusual enough to merit a report of the girl's case, by Rossbach and
several colleagues, in a medical journal.
But when the bone cancer reappeared last spring, in the form of a
baseball-size tumor in the girl's pelvic joint, her physicians held
out little hope. "We thought that was the end of her," said Rossbach.
"I didn't think we had anything to offer her."
Not knowing what else to do, Rossbach gave his patient a low dose of
radiation and a cancer drug called Etoposide, mainly as a palliative
for the child and her family. "But she couldn't tolerate those,"
Rossbach said, "and we had to stop. Honestly, I thought she would die
before a year."
A month ago, Rossbach received a call from the girl's family, but not
with the news he would have expected last spring. "They asked me if
she could go jogging," Rossbach said. "I told them OK."
Not prone to miracles
Ewing's sarcoma, which tends to strike adolescents, is a relatively
rare cancer. Only 25 cases were reported in Florida in 1997, according
to state cancer epidemiologists. For a first occurrence of Ewing's,
the overall survival rate is around 60 percent. In the pelvis, it is
even lower. When it recurs, the prognosis is extremely poor.
Cancer specialists avoid what they call "the c-word," pointing out
that no patient is deemed to have been cured until he or she dies,
cancer-free, of something else. Still, the visible tumor has been gone
from Rossbach's patient for more than nine months.
"We can't find any cancer," Rossbach said, while not ruling out the
possibility of unseen microscopic tumors elsewhere in her body. But
all that remains where the tumor once resided is a thin layer of scar
tissue that shows up on the girl's CAT scans. The question on
Rossbach's mind, and the minds of Northwestern University scientists
who have become intrigued by the surprising remission, is: Why?
Rossbach, who describes himself as "very conservative," isn't ready to
rule out the girl's last few radiation treatments or the abbreviated
course of Etoposide, even though he concedes that "most of the time
(Etoposide) doesn't work." Nor, Rossbach said, can he completely
discount the possibility that what has happened is "just a 'water
cure,' or a placebo therapy," unrelated to the girl's treatment.
But Rossbach's partner and colleague at All Children's, Dr. Jerry
Barbosa, is more sanguine.
"Dr. Rossbach is a very cautious individual," Barbosa said. "We don't
see miracles with this kind of cancer."
Other experts agree. "Ewing's sarcoma is not one of those cancers that
God is going to cure," said Dr. Edmund J. Doering, a Florida
oncologist who has treated many such cases and who puts the chances of
a spontaneous remission of pelvic Ewing's sarcoma at "zero."
Dr. Marc Lippman, director of the Lombardi Cancer Center at Georgetown
University in Washington, D.C., agrees. "Ewing's is not a tumor that's
associated with spontaneous remission," Lippman said, noting that a
recurring tumor is "very difficult to treat--very difficult."
A new hope
There is another possible explanation for the Tampa girl's remarkable
remission, one that lies in an equally remarkable coincidence of
timing.
Last May, after The New York Times published an article highlighting
the breakthrough cancer research of Harvard's Dr. Judah Folkman, the
non-scientific world learned of Folkman's 30-year crusade to prove
that cancerous tumors, at least in mice, could be made to shrink or
even to disappear by cutting off their blood supply.
Folkman's spacious lab at Children's Hospital in Boston is teeming
with brownish-black mice that testify to his theory, mice that once
bore huge tumors on their backs but now appear quite normal as they
scamper around plastic boxes filled with wood shavings and wait to die
of old age.
At the center of Folkman's discoveries are two naturally occurring
human proteins, which Folkman calls angiostatin and endostatin and
which appear to have starved those large and aggressive mouse tumors
into remission by halting the formation of new blood vessels the
tumors need to survive, a process known as angiogenesis.
Unlike existing cancer drugs, which target cancer cells directly,
mouse tumors do not appear to develop resistance to angiostatin or
endostatin. Nor do mice treated with those proteins show any sign of
toxic side effects. (See accompanying article.)
For these reasons and others, Folkman's research has given rise to
what is currently the hottest field in cancer research, currently
being pursued by scores of laboratories in this country and abroad.
Northwestern's pioneers
In the media storm that followed the Times article, a Tampa newspaper
asked Rossbach and Barbosa to write something about Folkman's
research.
"Quite frankly, I knew very little about it," Rossbach recalled.
"These things are not in the pediatric literature." Consulting the
scientific and medical databases, Rossbach found himself reading
"quite a lot on angiostatin and endostatin, and angiogenesis
inhibitors."
Among the articles that came to Rossbach's attention was a 1997 paper
published by a group of Northwestern University scientists led by Dr.
Gerald Soff. And in that coincidental encounter between a Florida
oncologist and a Chicago laboratory may lie the explanation for the
Tampa girl's remission.
In that article, Soff's group reported that it had succeeded in making
angiostatin with a less complicated method than the recombinant method
pioneered by Folkman: exposing naturally occurring plasminogen, the
abundant human protein of which angiostatin is a part, to enzymes that
cleave away the excess portions until only angiostatin remains.
Even more notable was the means by which that cleavage was achieved:
exposing plasminogen to drugs that have already been approved by the
U.S. Food and Drug Administration for other purposes.
One, called urokinase, belongs to a class of drugs called
thrombolitics, sold under names like tPA and streptokinase, that are
widely used as clot-busters and blood thinners, particularly in
treating heart attack victims.
The second class of drugs, free sulfhydryl donors, includes two
little-known medications--one for treating copper toxicity and another
for Tylenol overdoses--as well as a commonly prescribed blood pressure
medication, captopril, that was first shown to be an angiogenesis
inhibitor by Soff's Northwestern colleague, Noel Bouck.
The angiostatin derived by Soff's cleavage technique appeared to slow
the growth and reduce the spread of the same mouse tumors Folkman's
assistants were treating with the recombinant angiostatin made by
inserting the angiostatin gene into the DNA of a cell.
Last-ditch effort
When Chris Rossbach read about Jerry Soff's laboratory experiments
with urokinase and captopril, he immediately recognized the
possibility of a last-ditch treatment for his teenage patient, "a
therapy for a child who had no chances--or so at least we thought."
There was no laboratory-produced angiostatin available to treat the
girl, or any other patient. Even if there had been, no treatment would
have been possible without FDA approval.
But there was no ethical or legal bar to giving the girl captopril and
urokinase, in the hope that they might encourage the formation of
extra tumor-fighting angiostatin in her body.
In particular, there seemed to be no reason for concern about ill
effects from such therapy. Pediatric heart patients are sometimes
given captopril, and Rossbach notes that "we use urokinase all the
time for unclogging catheters" in children with cancer.
"Those were names I was familiar with," Rossbach says. "Kids were
getting these things without falling apart."
Although angiostatin-related therapy is not known to have been
attempted in humans, approval from the medical ethics committee at All
Children's Hospital was quickly forthcoming, as urokinase and
captopril are recognized as safe.
After the girl's insurance company refused to pay for her treatment,
Abbott Laboratories of North Chicago, which markets the urokinase
under the name Abbokinase, donated the drug.
Abbott says urokinase is "currently unavailable" because of concerns
by the FDA about some of the raw materials from which it is produced.
But Soff has reported achieving the same effect in the laboratory with
the other thrombolitics, tPA and streptokinase.
The tumor disappears
About a year ago, Rossbach began giving his patient six-hour
intravenous infusions of urokinase on consecutive days, each
accompanied by an oral dose of captopril. Slightly concerned about
using a blood pressure-lowering medication in a teenager with normal
blood pressure, Rossbach simply increased the amount of fluid in her
circulatory system.
There were no side effects from the therapy, Rossbach said--only an
utterly unexpected result. Two months after the treatments began, "the
tumor no longer looked like a tumor. It looked like an abscess. We put
in a needle, and pus came out."
Not long after that the tumor was gone. Although the girl's cancer
could return tomorrow, nearly 10 months later there is no sign of any
recurrence.
Though reluctant to credit the unconventional treatment until he has
further data, Rossbach is keeping his patient on the therapy. Once a
month, the girl makes the 30-mile journey from her Tampa home to All
Children's Hospital, where she receives a two-day infusion of
urokinase and a capsule of captopril.
After treating her last Monday and Tuesday, Rossbach pronounced the
girl "doing fine," with "no problems."
Meanwhile, Rossbach has shipped several samples of his patient's blood
to Soff's laboratory, where experiments are under way to characterize
the biochemical effects of the treatment.
Rossbach cautions, however, that even if the girl's blood contains
evidence that her angiostatin level was indeed boosted during the
treatment, that would still not be definitive proof that the treatment
itself was responsible for her remission.
In fact, no such proof is possible without an organized trial in which
randomly chosen groups of patients are treated with new and existing
therapies side-by-side. (See accompanying article.)
Soff, who says he hopes to begin testing the urokinase-sulfhydryl
"cocktail" in such a trial at Northwestern before the end of the year,
agrees that "one case doesn't make a proof."
Noting that angiostatin by itself hasn't made mouse tumors vanish
completely in Folkman's lab, only reduced them to dormancy, Soff
cautions that, "If we're seeing tumors basically dying, it's got to be
something more than just our cocktail."
One possibility, suggested by Soff and acknowledged by Rossbach, is a
"synergistic" reaction between the cocktail and the girl's previous
radiation therapy. Last year, researchers at the University of Chicago
reported substantial and unexpected shrinkage of tumors in mice after
treating them with low doses of radiation and injections of Soff's
plasminogen-derived angiostatin.
Folkman predicts that, if angiostatin and endostatin have a role in
cancer treatment, it will be in combination with radiation and
existing cancer drugs. But even if an angiostatin-generating cocktail
ultimately proves successful in treating some cancer patients--and
that is still an enormous "if"--such a treatment will not necessarily
work in all patients, or even most.
Isaiah J. Fidler, a senior cancer researcher from M.D. Anderson in
Houston, warns that it is "biologically impossible" for any single
treatment, however successful, to have an impact on every kind of
tumor in every organ of the body.
"Don't be depressed when you see a paper that says, 'We cured cancer,'
" Fidler advised colleagues attending a medical meeting in
Philadelphia last month. "No, we didn't. Everybody here will have a
job for years to come."
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