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Timing appears essential to combining
antiangiogenesis and radiation therapy
MGH study provides clues to best
therapeutic schedule, cellular underpinnings of treatment
BOSTON - December 20, 2004 - Although the earliest clinical
trials of the cancer-fighting potential of antiangiogenesis drugs
did not have the dramatic results that some hoped for, subsequent
trials showed that combining agents that suppress blood-vessel growth
with therapies that destroy cancer cells can improve patient survival.
In the December issue of Cancer Cell, researchers from the
Massachusetts General Hospital (MGH) describe how timing may be
crucial to successfully combining angiogenesis inhibitors with radiation
treatment and reveal more about exactly how these drugs work to
fight cancer, which is somewhat different from earlier theories.
"The blood vessels that develop to supply nutrients to a tumor
are not normal," says Rakesh Jain, PhD, director of the Steele
Laboratory in the MGH Department of Radiation Therapy, the study's
senior author. "The vessels are leaky, dilated, disfigured,
and do not evenly inflitrate the tumor, which can interfere with
standard cancer therapies. Chemotherapy drugs are not distributed
throughout the tumor, and the oxygen level is low, making tumors
resistant to radiation therapy. It now appears that antiangiogenic
therapy transiently improves a tumor's blood supply and oxygenation,
making it more vulnerable to radiation therapy."
Although some animal studies have suggested that combining antiangiogenesis
and radiation therapy can slow tumor growth, in others the treatment
appeared to spur tumor growth. The current investigation was designed
to resolve these conflicting results and to improve understanding
of the cellular and molecular underpinnings of antiangiogenesis
treatment. The MGH researchers implanted human brain tumor tissue
into mice that were then treated with various combinations of an
angiogenesis inhibitor called DC101 and radiation therapy.
DC101 alone produced a minor delay in tumor growth, and radiation
alone produced a more significant growth delay. But of five different
schedules of combined treatment, only giving radiation from 4 to
6 days after initiation of DC101 therapy resulted in a synergistic
effect that was greater than simply adding the effects of both treatments.
Measurement of the oxygen levels within tumor tissue supported the
theory that DC101 improves oxygen delivery to the tumor during the
same time period, with hypoxia (oxygen starvation) almost eliminated
on day 5 but returning by day 8.
To better understand the mechanism behind these changes, the researchers
conducted several detailed analyses of the tumor tissue. They observed
a shift toward more normal blood vessels that were smaller and less
disfigured after DC101 treatment and also found that these vessels
had been stabilized by the recruitment of pericytes - cells that
normally help to support blood vessel walls. Mirroring the pattern
of oxygen supply, pericyte coverage of blood vessels peaked around
day 5 and then fell off by day 8.
The investigators also showed that greater pericyte coverage was
the result of more pericytes being attracted to the tumor vessels,
rather than the removal of pericyte-poor vessels as some researchers
had assumed. Measurement of a factor known to be involved in pericyte
recruitment found that its levels were temporarily increased after
DC101 treatment. Examination of the effects of DC101 on vascular
cells' basement membrane, which becomes abnormally thick in tumors,
indicated that the membrane was thinner during the day-2-to-day-5
time period and also showed that this improvement resulted from
the increased activity of specific enzymes.
One crucial result of these findings is alleviation of the concern
that reducing a tumor's blood supply would actually worsen hypoxia
and increase resistance to radiation therapy. "The success
of this treatment approach depends on carefully scheduling when
radiation is administered to take the greatest advantage of this
window of vascular normalization," says Jain, who is Cook Professor
of Tumor Biology at Harvard Medical School. His group plans further
studies to determine how these results could be applied to treatment
of cancer patients.
Additional authors of the current study are co-first authors Frank
Winkler, MD, PhD, and Sergey Kozin, PhD, along with Ricky Tong,
Sung-Suk Chae, PhD, Michael Booth, PhD, Igor Garkavtsev, MD, PhD,
Lei Xu, MD, PhD, Dai Fukumura, MD, PhD, Emmanuelle di Tomaso, PhD,
and Lance Munn, PhD, all of the Steele Laboratory at MGH; and Daniel
Hicklin, PhD, of ImClone Systems Incorporated in New York. The work
was supported by grants from the Goldhirsh Foundation and the National
Cancer Institute.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $400 million
and major research centers in AIDS, cardiovascular research, cancer,
cutaneous biology, medical imaging, neurodegenerative disorders,
transplantation biology and photomedicine. In 1994, MGH and Brigham
and Women's Hospital joined to form Partners HealthCare System,
an integrated health care delivery system comprising the two academic
medical centers, specialty and community hospitals, a network of
physician groups, and nonacute and home health services.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
Information about Clinical Trials
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