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Study identifies another strategy for
normalizing tumor blood supply
Controlling nitric oxide levels
could further improve effectivness of anticancer therapies
BOSTON - February 20, 2008 - Manipulating levels of nitric
oxide (NO), a gas involved in many biological processes, may improve
the disorganized network of blood vessels supplying tumors, potentially
improving the effectiveness of radiation and chemotherapy. In an
upcoming issue of the journal Nature Medicine, researchers
from the Steele
Laboratory of Radiation Oncology at Massachusetts General Hospital
(MGH) report an experiment in which NO production was selectively
suppressed in tumor cells while being maintained in blood vessels.
The result was a significant improvement in the appearance and function
of the tumor's blood supply.
"Our finding suggest that the creation of perivascular NO
gradients - differences between the levels produced in blood vessels
and those found in tumor tissue - may be able to normalize tumor
vasculature," says Dai
Fukumura, MD, PhD, of the Steele Laboratory, who led the study.
"Combining the use of angiogenesis inhibitors, which normalize
vasculature through a different mechanism, with the blockade of
nonvascular NO production may produce even greater improvement in
therapeutic outcomes."
The blood vessels that develop around and within tumors are leaky
and disorganized, interfering with delivery of chemotherapy drugs
and with radiation treatment, which requires an adequate oxygen
supply. Combining angiogenesis inhibitors, drugs that suppress the
growth of blood vessels, with traditional anticancer therapies has
improved patient survival in some tumors. That success supports
a theory developed by Rakesh
K. Jain, PhD, director of the Steele Laboratory, that the agents
temporarily 'normalize' blood vessels, creating a period during
which other treatments can be more effective.
Since angiogenesis is one of many physiologic activities mediated
by NO, the MGH research team hypothesized that restricting NO production
to blood vessels also could improve tumor vasculature. Using cancer
cells from human brain tumors, they suppressed the enzyme that controls
NO production in nonvascular tissue. When the modified tumor cells
were implanted into mice, analysis of the resulting tumors showed
that NO was present primarily in blood vessels, with significant
reductions in tumor cells. Vessels in the growing tumors were more
evenly distributed and less distorted than those in tumors grown
from untreated tissue.
"Angiogenesis inhibitors block formation of new vessels by
directly or indirectly inhibiting the proliferation and survival
of vascular endothelial cells. But since their overall effect is
to reduce the density of blood vessels, the ability of those agents
to normalize tumor vasculature may not last long," says Fukumura.
"Blocking nonvascular NO production and maintaining NO levels
around the vessels appears to keep endothelial cell function at
the proper level." An associate professor of Radiation Oncology
at Harvard Medical School, Fukumura notes that the strategy now
should be investigated in other types of tumors.
The Nature Medicine report has been released online and was supported
by grants from the National Cancer Institute. In addition to Fukumura
and Jain, co-authors of the article are first author Satoshi Kashiwagi,
MD, PhD, Kosuke Tsukada, PhD, Lei Xu, MD, PhD, Junichi Miyazaki,
MD, PhD, Sergey Kozin, DSc, PhD, James Tyrrell, PhD, and Leo Gerweck,
PhD, all of the Steele Lab; and William Sessa, PhD, Yale University
School of Medicine.
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 $500 million
and major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, systems biology, transplantation biology and photomedicine.
Media Contacts: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
Information about Clinical Trials
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