Experimental Compound Reduces Lung Damage After Radiation
DURHAM, N.C. -- A single dose of an experimental compound called 1D11 successfully prevented severe lung damage from occurring in mice that underwent radiation therapy to treat lung cancers. The researchers from the Duke Cancer Institute who performed the experiments say the same potential exists to decrease lung injury -- and potentially heal existing damage -- in humans receiving radiation.
Clinical trials in humans should begin within two years, said the research team.
Radiation is effective at killing cancer cells, but the high doses required to subdue cancer also damages nearby healthy tissue. Efforts to prevent such damage have increased as cancer patients are living longer and quality of life has become a major focus of cancer therapies, said the radiation oncologists.
The Duke team used the experimental compound 1D11 to block a protein in cancer cells, TGF-beta, which promotes cancer growth once a tumor has begun to grow. Cancer cells over-produce TGF-beta, which in turn promotes the formation of scar tissue in the lungs. TGF-beta also fuels the growth of blood vessels that feed cancerous tumors, among a range of other activities inside cells.
Thus, inhibiting TGF-beta production has dual benefits: it ameliorates lung tissue damage also slows the growth of cancer cells, they said.
Results of the study, conducted by Mitchell Anscher, MD, and Zelijko Vujaskovic, MD, Ph.D., are being presented at the annual meeting of the American Society for Therapeutic Radiology and Oncology in Denver, Oct. 16 – 20, 2005.
The researchers administered the compound – an anti-body that scavenges excess TGF-beta – to the mice immediately after the last of five doses of radiation. The treated mice demonstrated significantly less of the complications usually seen after radiation, including shortness of breath, scar tissue formation, and the influx of inflammatory cells called macrophages. When scar tissue forms, the lung walls become thicker and they lose their ability to transfer oxygen into the bloodstream, said the researchers.
Results from the study also suggest that the experimental compound could reduce lung damage that has already been sustained, said Anscher, a Duke radiation oncologist.
"It was once thought that radiation fibrosis – scar tissue formation – was irreversible, but this is proving not to be the case," he said. "We've learned that radiation damage is a dynamic process that is continually evolving months or even a year after radiation exposure."
"We're investigating at what point we can start therapy with the TGF-beta antibody to prevent or reverse some of the damage that has occurred," said Vujaskovic, a Duke radiation oncologist and cancer biologist.
Within fractions of a second- of exposure to radiation, the body begins to produce oxygen free radicals – unstable and reactive molecules that attack nearby stable molecules and eventually disrupt and damage cells and tissues. Production of free radicals continues for many months following radiation, up to or beyond a year, and is responsible for much of the chronic lung injury seen in patients who have been irradiated.
Moreover, free radicals appear to trigger an even higher level of TGF-beta production, so blocking this protein is even more critical after radiation, said Anscher. He noted that the Department of Homeland Security has demonstrated interest in compounds that block radiation damage in the event of a nuclear or radiologic terrorist attack.
"Questions we ultimately hope to answer include, 'whether these compounds protect against whole body irradiation,' and 'what is the hierarchy of radiation damage to the body in terms of its impact on the bone marrow, the lungs, the intestines, the kidneys,'" said Vujaskovic.
Because TGF-beta is over-expressed in many cancers, blocking its expression has been the focus of numerous scientific studies. In the current study, one single dose of 1D11 produced the protective effects on the lungs. Multiple doses at varying points after radiation could further mitigate radiation damage to the lungs, said Vujaskovic.
The study was funded by Genzyme, maker of the experimental compound.