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I read the following on another site and I thought it was very interesting, especially because it involves Judah Folkman who, as far as what I've read, is enormously respected...
Cancer drug given new life (Feb 2004) Its toxic side effects eliminated
By William J. Cromie Harvard News Office
The cancer drug's effectiveness surprised everyone. Called TNP-470, it
stunted the growth of every malignancy it touched - animal tumors, human
tumors, and spreading tumors. It suppressed tumors of the ovaries,
colon, prostate, and breasts. In some cases the tumors shrank; in
others, they disappeared.
But it was too good to last. Some patients whose malignancies were
repressed, even eliminated, started showing unacceptable side effects -
problems with motor coordination, seizures, and malaise.
TNP-470 was developed by Donald Ingber and Judah Folkman of Harvard
Medical School, two of the best in the business of cancer research.
Folkman, Andrus Professor of Pediatric Surgery and professor of cell
biology, had discovered that cancers could be starved to death by
cutting off the growth of blood vessels they depend on for nutrition. In
his laboratory at Children's Hospital in Boston, he and his colleagues
produced several drugs that stifled the growth of such vessels. TNP-470
seemed to be the most effective.
"It's a wonderful drug," Folkman comments. "It inhibits growth of
the largest variety of different tumor types of any drug yet tested.
It works on metastatic (spreading) tumors. It's rare that a drug
does that."
So the side effects were a crushing setback. Folkman discussed the
problem with Ronit Satchi-Fainaro, a young chemist he recently hired as
a research fellow. "I can fix the problem," she told him.
Satchi-Fainaro realized that TNP-470 molecules are too small. They slip
easily into leaky new blood vessels growing into tumors; that's what
made the molecules so effective. But they also penetrate healthy cells.
The researchers found them in the spinal fluids of test animals. Their
assault on nervous tissue was interfering with motor coordination and
producing seizures. Her solution: bulk up the molecules; make them too
big to get into any place but the tumor blood vessels.
It sounded too simple. But, Folkman admits, "Ronit knew more chemistry
than I did. That's why I hired her." He told her to go ahead.
A big surprise
The idea worked. The jumbo drug technically known as the new conjugated
TNP-470, slows the growth of deadly skin cancer (melanoma) and lung
tumors in mice. Unlike free TNP-470, it's too big to have toxic effects
on the nervous system. The motor coordination of the mice is fine and
they develop normally.
Satchi-Fainaro, Folkman, and their colleagues describe the success in
the March issue of Nature Medicine. While waiting for publication of the
report, the team tried jumbo TNP-470 in other cancers, including
spreading lung tumors in mice. It works well. "Frankly, it was a big
surprise; we didn't expect the results to be so good," Folkman says.
"The conjugated drug molecules are too big to seep from normal blood
vessels," Satchi-Fainaro explains. But they easily dribble out of leaky
new blood vessels and into the tumors. "Once inside the tumors, the
copolymer [added baggage] is cleaved chemically, and the TNP-470 can do
its work. It stays longer in the tumor than the free molecule, so it's
more effective."
Will they now try jumbo 470 in humans? "Absolutely," Folkman answers
quickly. "Those who did the human trials with the free TNP-470 are
eager to try the conjugated drug." These include cancer researchers
at Dana-Farber Cancer Institute in Boston, a Harvard teaching
hospital two blocks from Folkman's lab, and the M.D. Anderson Cancer
Center in Houston.
That doesn't mean that it will soon be available to patients. "We have
to start the testing all over again," Folkman points out. First there
will be safety tests, then efficacy tests; small groups of patients,
then larger groups. "It'll be several years before we can get FDA (Food
and Drug Administration) approval." He says that's "frustrating," but he
has his game face on.
Folkman sees jumbo TNP-470 being used together with other drugs. One
example is Avastin, another blood-vessel wrecker based on his research
that was approved Feb. 26 by the FDA. At Dana-Farber Cancer Institute,
Avastin, combined with chemotherapy, is being tested on runaway breast
cancer. Chemical therapy has tough side effects, so doctors give
patients a chance to rest between doses. But blood vessels grow back
during such intervals, making it more difficult to stop the spreading
cancer. Now they use Avastin every day to choke and starve tumor cells.
Folkman pushes across the table a list of 17 different human tumors that
respond to free TNP-470. Another list shows that the drug halts the
spreading of five different lung and liver cancers. "That's amazing," he
comments. "We expect the conjugated drug will perform better in these
and other cancers."
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