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| Medical Pike Briefs : Headline Index : Clinical Trial | |||
Combretastatin,
from African
November 23, '98 A substance found in the bark of an African willow
tree boosts the tumor-cell killing power of radiation therapy as much as
500 times in laboratory animals, University of Florida researchers report
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The possible advantage of using combretastatin with radiation (or chemotherapy)
was demonstrated in preclinical research at the University of Florida.
The research was paid for by OXiGENE, Inc., the Swedish/ Boston company
that makes the drug.
"We are always pursuing new avenues to enhance
our conventional cancer therapies, radiation and chemotherapy," said
Dietmar Siemann, a professor of radiation oncology in UF's College of
Medicine. "The results with combretastatin A-4 prodrug are very encouraging.
We're able to achieve these effects by giving relatively low doses that
produce no side effects in mice," Siemann said.
If Phase I trials show human patients can tolerate
the drug, more clinical testing will be done. Phase II trials will look
for a measurable effect on patient's tumors. If combretastatin is safe,
tolerable and effective, Phase III trials will see if it benefits patients
as much as standard treatments.
Attacks
Tumor's Existing Blood Supply
Combretastatin, found in the bark of the African bush
willow tree Combretum caffrum, was identified a decade ago by George
R. Pettit at Arizona State University. Like other new compounds that indirectly
fight tumors, combretastatin targets blood vessels that sprout up to nourish
cancerous growths. The idea of shrinking tumors by attacking their life
support system has been championed by Judah Folkman, a physician and cancer
researcher at Children's Hospital in Boston who has received worldwide
attention for his work.
"The combretastatin approach is a little different
from what Dr. Folkman has been doing," said Siemann. "The majority
of research has focused on preventing the growth of new tumor blood vessels,
the anti-angiogenesis strategy. What we are doing is attacking existing
and newly formed tumor blood vessels directly by exploring a key difference
between these vessels and those found in normal tissues."
Tumor vessels contain lots of dividing blood vessel
cells. "We and others have shown that these dividing cells can be
selectively damaged by combretastatin," Siemann said. "This
approach leads to rapid and catastrophic shutdown in the vessels that
serve the tumor, resulting in extensive tumor cell death."
Twenty-four hours after Siemann dosed mice with the
compound, the damage to the cancer's blood vessels was so extensive that
viable tumor cells were seen only at the outside edges of the tumors.
Siemann believes that these tumor cells survived because at its surface,
a tumor is sustained by the body's normal blood vessels rather than those
that have developed specifically to support the cancerous growth. Normal,
non-dividing blood cells are not susceptible to combretastatin.
"The strategy is to kill those surviving tumor
cells with conventional treatment, such as radiation therapy or chemotherapy,"
he said. Combretastatin also was able to kill off oxygen-starved tumor
cells, which resist radiation and some forms of chemotherapy, Siemann
said.
A Danish study parallel with Siemann's research found
that combretastatin was effective against both implanted and spontaneous
tumors in animal models. The Danish study says the effects on "spontaneous"
tumors is particularly "compelling " because these are more
akin to what will be targetted in human patients. At the same time, as
Dr. Judah Folman always emphasizes, so far all the work has been done
only in mice.
Dr. Scot C. Remick, M.D. is program leader for developmental therapeutics
at the Ireland Cancer Center, Cleveland and associate professor of medicine
at Case Western Reserve University School of Medicine.
Dietmar Siemann, his graduate student Lingyun Li and pathologist Dr.
Amyn Rojiani, of the Moffitt Cancer Center in Tampa, are publishing a
paper on their work in the November issue of the International
Journal of Radiation Oncology, Biology, Physics.
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