Nitric Oxide Finding May Yield Better Cancer Treatments and Blood Substitutes
DURHAM, N.C. -- Duke University Medical Center researchers
have demonstrated how to safely deliver more oxygen to
oxygen-deprived tissues in the body, a finding that could lead
to more effective blood substitutes, wound healing therapies
Oxygen is critical to proper functioning and healing of all
tissues in the body, but altering its levels with current
therapies can elevate blood pressure and constrict blood
vessels – serious risks for heart disease. Additionally, such
effects reduce the efficacy of many cancer therapies, including
radiation and some forms of chemotherapy.
The Duke team showed that simply adding a molecule called
nitric oxide to the blood's hemoglobin can make it deliver more
oxygen to tissues -- without boosting heart rate or
constricting blood vessels. Hemoglobin is the blood's
Results of the study by Duke and Howard Hughes Medical
Institute researchers are reported in the May 27, 2005, issue
of Circulation Research. The study was led by Mark Dewhirst,
D.V.M., Ph.D., the Gustavo S. Montana Professor of radiation
oncology; and Jonathan Stamler, M.D., Howard Hughes Medical
Institute investigator and professor of medicine.
"Hemoglobin needs its natural partner in the blood, nitric
oxide, to do its job of delivering oxygen to tissues, but
current treatments deliver hemoglobin without nitric oxide,"
said Dewhirst. "Hemoglobin by itself actually reduces
oxygenation to tissue because it constricts blood vessels,
reducing blood flow." Thus, when delivered alone, hemoglobin
may cause potentially fatal side effects and limit the
effectiveness of radiation and chemotherapy.
The Duke researchers were seeking ways to improve oxygen
levels inside tumors, which are often "hypoxic" or low in
oxygen. These tumors are more resistant to treatment with
chemotherapy or radiation, said Dewhirst.
"If we could raise the level of tumor oxygenation before
radiation, we would have a better chance of killing more of the
cancer cells," added Dewhirst.
The team hypothesized that hemoglobin containing nitric
oxide would hold onto its oxygen until reaching the hypoxic
environment of the tumor. Once there, it would release nitric
oxide and dilate blood vessels to increase oxygen delivery.
The researchers confirmed this scenario by comparing the
effects in animals of pure oxygen versus injections of combined
hemoglobin and nitric oxide. The pure oxygen, breathed in
naturally, raised the level of circulating oxygen, but not
oxygen levels in the arteries feeding the tumor. The hemoglobin
plus nitric oxide, by contrast, raised oxygen levels in the
The result supports the theory that hemoglobin senses oxygen
levels and holds on to its nitric oxide and oxygen when oxygen
levels in tissue are high, but releases oxygen and nitric oxide
when oxygen levels are low, said Pierre Sonveaux, Ph.D., a
post-doctoral fellow in Dewhirst's laboratory.
"This is the strongest proof yet that hemoglobin senses
oxygen levels and unloads nitric oxide when oxygen levels are
low," said Sonveaux. "These results open up the possibility of
using nitrosohemoglobin therapeutically in patients where there
is not adequate oxygen perfusion to tissue." Nitrosohemoglobin
(SNO) is the combination of nitric oxide and hemoglobin.
The team's finding is the strongest evidence to date
supporting Stamler's theory, first developed in 1996, that
nitric oxide is an innate part of the body's oxygen delivery
system. In previous studies, Stamler and his colleagues
demonstrated that nitric oxide in blood cells is an active
regulatory molecule that senses the oxygen level in tissue and
causes hemoglobin to undergo subtle shape changes to release
its oxygen in tissues when levels are low.
The study was funded by grants from the National Institutes
of Health. Sonveaux is a fellow of the Belgian American
Educational Foundation (BAEF) and a "Fonds National de la
Recherche Scientifique" (FNRS) post-doctoral fellow detached
from the University of Louvain Medical School, Belgium.