Oxygen boost unlocks key to combining cancer treatments

By Debbie Bolles / April 11-20, 2011

With so many choices at a doctor’s disposal, finding the most effective cancer treatment often means weighing therapeutic options against how they may interact.

Take radiation therapy. This type of treatment works best when there’s plenty of oxygen in the tumor. Very effective drugs called vascular disrupting agents (VDAs), however, attack a tumor’s blood vessels, cutting off their oxygen supply. So, these two therapies could potentially work against each other.

That’s the conundrum that UT Southwestern’s Dr. Dawen Zhao, associate professor of radiology, and Dr. Ralph Mason, professor of radiology, attempted to solve through a recently published study on cancer treatment in rats that was funded by an IDEA award from the Department of Defense breast cancer initiative.

“If you destroy the blood vessels, you cut off the oxygen. In a way, then, the therapies may be working against each other,” said Dr. Mason, senior author of the study available online and scheduled for the June 1 issue of the International Journal of Radiation Oncology, Biology and Physics. Dr. Zhao was lead author.

The researchers found a solution by adding oxygen to the therapy regimen. Then, using a vascular disrupting agent, radiation and the addition of using oxygen, breast cancer growth in rats was slowed fivefold compared with using the drug alone.

“The goal here wasn’t complete cure, but enhanced response,” said Dr. Mason. “We were looking for the optimal combination.”

Researchers used the vascular disrupting agent Combretastatin A4 phosphate (CA4P), an agent derived from the African bush willow. CA4P is currently being evaluated in clinical trials to study its potential in the treatment of lung cancer and anaplastic thyroid cancer.

The research team studied various combinations of CA4P and radiation. They then added oxygen. After testing seven combinations of the drug, radiation and oxygen under different timing sequences, the research team found an effective formula — administering the drug, followed by a single dose of radiation 24 hours later during oxygen therapy.

Treatment combinations tested included CA4P only, radiation only and CA4P plus radiation. Tumor growth slowed in the animals treated with the drug alone, but only for a few days. Another group treated solely with radiation fared somewhat better, but not as well as the group treated with all three.

“This suggests a role for oxygen-sensitive measurements in developing combined therapy and potentially optimizing treatment of patients,” Dr. Zhao wrote in the article’s conclusion.

The study, which lasted about a year, used near-infrared spectroscopy and MRI technology to measure tumor blood oxygenation changes and the slowdown or death of cancer cells. Researchers collaborated with biomedical engineering scientists at
UT Arlington, who provided some of the testing equipment.

Dr. Mason said researchers will now study this treatment regimen’s effects on other cancer types.

Other UT Southwestern researchers who participated in the study were Dr. Cheng-Hui Chang, clinical associate professor of radiation oncology, and Dr. Hanli Liu, professor of biomedical engineering at UT Arlington and adjunct professor at UT Southwestern. The drug CA4P was supplied by OxiGene of Waltham, Mass.