Apr. 15, 1999 PHILADELPHIA - In a discovery that might help explain why widely used cancer therapies are less than optimal, Duke University Medical Center researchers have found that a tumor's oxygen level and blood flow can fluctuate rapidly.
The Duke animal study, which contradicts previous assumptions about tumors, could be important because the two major cancer treatments, radiation and chemotherapy, depend on a constant high oxygen level and steady blood flow within a tumor, scientists said.
"These fluctuations in oxygen level and blood flow are not predictable and might represent an impediment to radiation therapy and drug therapy," said Mark Dewhirst, co-director of the radiation oncology and hyperthermia program at Duke Comprehensive Cancer Center and associate professor of pathology. "Before this work, there was no way to reliably measure these values."
Dewhirst prepared the findings for presentation Tuesday at an American Association for Cancer Research meeting. His study, which was done in collaboration with Rod Braun, assistant professor in radiation oncology, was funded by the National Cancer Institute. A report based on the results of this study has been accepted for publication by the American Journal of Physiology.
High oxygen levels are crucial for effective radiation therapy, Dewhirst explained, because radiation kills tumor cells by forming oxygen radicals - highly reactive oxygen atoms that damage DNA.
Chemotherapy might be affected by the fluctuations, Dewhirst said, because if tumor blood flow drops, the drugs might not be delivered efficiently throughout the tumor.
While low oxygen levels, called hypoxia, are known to exist in certain tumors, researchers had not measured changes in oxygen levels over time. In the current study, Dewhirst and his colleagues measured oxygen levels in mammary tumors in seven rats using an electrochemical probe that produces an electrical current depending on the amount of oxygen present in the tissue.
The scientists found unexpectedly that no tumor had stable oxygen levels. According to Dewhirst, 60 percent of their measurements demonstrated acute hypoxia - in which oxygen levels dipped below the cutoff point for hypoxia of 10 mm of oxygen pressure. A full 25 percent of measurements were chronically hypoxic - never above 10 mm of oxygen - a condition known to increase tumor radiation resistance. The remainder, 15 percent, had oxygen levels that were always higher than 10 mm but still were not stable.
The clinical implications of such fluctuations could be serious, Dewhirst said. For example, fluctuations from low to high oxygen levels might reduce sensitivity to radiation, even for those tumors usually above hypoxic levels.
In particular, the large fluctuations might be enough to simulate a condition called "hypoxia-reoxygenation injury" that can occur when oxygen levels increase in oxygen-starved tissues, Dewhirst said.
When oxygen is suddenly restored to an oxygen-deprived area, an enzyme called xanthine oxidase produces oxygen radicals from the newly supplied oxygen, leading to tissue damage. This hypoxia-reoxygenation injury can occur in conditions such as a stroke: a brain region already damaged by low-oxygen from the cutoff of blood flow can suffer additional damage when oxygen is restored, due to xanthine oxidase.
Cells that survive hypoxia-reoxygenation injury are likely to have developed defenses against damage from oxygen radicals, Dewhirst said. Likewise, tumor cells could develop protection against oxygen radicals if the oxygen level fluctuation is enough to mimic hypoxia reoxygenation. Thus, even if the tumor is irradiated at a time when the oxygen level is high and radiation should work, the tumor might not respond to therapy.
To understand whether such fluctuations also are present in other tissues, the researchers compared measurements in tumors to those in rat leg muscle. While they found similar frequencies of fluctuations in both tissues, the size of the fluctuations was much larger in tumor than in muscle, Dewhirst said.
He speculates that a phenomenon known as "vascular remodeling" -- in which blood vessels are formed and die quickly, quickly changing blood flow patterns within a tumor -- might underlie the mechanism responsible for the rapid, large fluctuations within tumors.
Another hypothesis is that the low tumor oxygen levels might stimulate structural changes in red blood cells, causing the blood to thicken and thus reducing blood flow.
The researchers still have to test these ideas. In further research, they will evaluate the different mechanistic possibilities in their rat model by blocking the involved pathways. For example, to test the impact of vascular remodeling, they plan to use "angiogenesis" inhibitors -- chemicals that prevent new blood vessels from forming.
The researchers also will seek to discover whether their findings in the rat tumors apply to other tumors and other animals. A collaboration with the North Carolina Veterinary School in Raleigh will allow them to take measurements on dogs who are routinely brought in for cancer treatment.
Dewhirst emphasized the importance of making measurements of tumor oxygenation and blood flow in human tumors as soon as the technology is available.
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