Nitric Oxide Finding May Yield Better Cancer Treatments And Blood Substitutes

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 oxygen-carrying component.

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 tumors.

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.