Anticancer Agent Appears to Enhance Radiation's Effects in Mice
By NICHOLAS WADE
Tests of a promising anticancer agent known as angiostatin have shown
that it enhances the effects of radiation in treating human tumors
grafted into mice.
The mechanism of the effect is unknown, but the agent seems to make
the blood vessels that supply the tumor more sensitive to radiation.
Angiostatin, a substance produced by the body, belongs to a class of
agents called anti-angiogenesis factors, meaning that they suppress the
formation of new blood vessels. The exploration of such agents in cancer
treatment has long been advocated by Dr. Judah Folkman, in whose
laboratory angiostatin and another angiogenesis inhibitor, endostatin,
were discovered.
Folkman, of Children's Hospital in Boston, described the new result,
being published Thursday in the journal Nature, as "very clever and very
interesting."
"The implication for translation to the clinic," he said, "is that
anti-angiogenesis therapy with angiostatin could be very useful with
radiation."
Dr. Jay Harris, chief of radiation oncology at the Dana-Farber Cancer
Institute in Boston, said the study "creates a whole new way of thinking
about how radiation works."
Radiation therapists have focused on trying to kill as many tumor
cells as possible, Harris said, but the new finding raises the
possibility that "a significant part of the benefit from radiation comes
from killing the blood vessels that supply a tumor's growth."
The senior author of the study, Dr. Ralph Weichselbaum, a radiation
oncologist at the University of Chicago, said the research had found
that the combination of angiostatin and radiation was more effective
than either alone in shrinking the mice tumors.
He said he had not had enough angiostatin to determine whether it
would have eliminated the tumors entirely in a prolonged experiment. He
added that he had achieved even better results with endostatin, in
experiments that have yet to be published.
The finding that angiostatin and radiation were far more effective in
combination than was either agent alone would, if applicable to humans,
be important for therapists.
Several substances successfully attack tumors in mice but turn out to
be useless in treating human cancers. One reason is that tumors are
genetically unstable and quickly develop resistance to many agents that
attack them.
Considerable interest has been evoked by Folkman's work, particularly
because in a journal article on angiostatin last November he and his
colleagues showed how the resistance problem could perhaps be
sidestepped.
The key to the possible solution is that angiostatin does not attack
the tumor cells themselves but affects the cells that form the blood
vessels supplying the tumor. The blood vessels' walls are composed of
normal, noncancerous cells known as endothelial cells. Being normal, the
endothelial cells are thought to be incapable of developing resistance.
Folkman said he had always envisaged that angiostatin and related
agents would supplement, not replace, anticancer treatments like
radiation and chemotherapy.
"As a platform," he said, "it's not exclusive."
Weichselbaum said he hoped to try his combination method in humans.
One obstacle is that angiostatin is at present available only in
quantities sufficient for research on mice.
Dr. Gerald Soff, a co-author who supplied the angiostatin for the
study, said that he could not scale up his production without a
commercial partner and that the rights to angiostatin as a human therapy
were held by Entremed, a company that holds licenses to Folkman's work.
But Soff, a biologist at Northwestern University Medical School in
Chicago, also said that the version of human angiostatin that he makes
in his laboratory differs in structure from the human version made by
Entremed. If so, his institution might be able to license a competing
version.
Weichselbaum, Soff and Folkman do not know how it is that angiostatin
enhances the effect of radiation. Radiation is usually thought to be
effective only against actively dividing cells. Angiostatin is thought
to work by inhibiting the growth and division of endothelial cells.
Hence angiostatin might be expected to deprive radiation of any
targets at all. The work of Weichselbaum and Soff shows that empirically
the opposite is the case, but the explanation for this surprising result
remains to be found.
Critics of the anti-angiogenesis approach have said that it may be
useful in preventing new tumors or the spread of old ones, because these
tumors must induce new blood vessels to bring them nutrients, but that
there is no reason it should work against established tumors, which
already have a blood supply.
But Folkman said that according to his experiments, even established
tumors have a rapid turnover of blood vessels and must continually
induce the body to build new ones. Even established tumors, then, should
in principle be vulnerable to anti-angiogenesis factors.
Anti-angiogenesis has become a fast-moving field, with two new
journals devoted to the subject and a raft of companies and researchers
now exploring a variety of chemicals with angiogenesis-suppressing
properties.
Angiostatin and endostatin, two natural products, seem to be the most
potent in laboratory tests, but they are proteins and hard to make in
large quantity.
Thursday, July 16, 1998
Copyright 1998 The New York Times
--
Robert W. Atcher, Ph.D.
Chemical Science and Technology Div.
CST-18, MS J514
Los Alamos National Laboratory
Los Alamos, NM 87545
505 667 0585 Voice
505 665 4955 FAX