The therapy has not yet been tested in humans, and is probably years away from clinical application. But Avraham Dilmanian, the scientist leading the studies, says, "The hope is that eventually, we will be able to use microbeam arrays to destroy pediatric brain tumors, or at least significantly delay their growth, without damaging as much surrounding tissue as conventional broad-beam x-rays do."
The scientists are specifically looking for a treatment for brain tumors in infants and young children because their developing brains are particularly susceptible to radiation damage. As a result, conventional radiation therapy cannot be used before the age of 3, and is used judiciously afterward.
In MRT, the x-rays are confined to very thin slices of planar beams arranged in parallel arrays with spaces in between -- like the parallel panels of open vertical blinds. As a result, the x-rays irradiate only about 1/3 of the tissue, and the areas between the beam slices receive very little radiation. The technique was first developed at Brookhaven's National Synchrotron Light Source (NSLS) in the early 1990s, and is still under investigation there and at the European Synchrotron Radiation Facility in Grenoble, France. Unlike x-ray sources used in clinical radiation therapy, only high-intensity synchrotron sources can be used to confine the beam to the extremely narrow slices with very high dose rates that are needed for MRT.
In the current study, the scientists used a single exposure to irradiate the entire brains of duck embryos three to four days before hatching. One-third of the embryos received microbeam radiation at in-beam doses of 40, 80, 160 or 450 Gray (Gy), the international unit for measuring absorbed radiation doses (1 Gy = 100 rad). The highest dose served as a high-end control. Another third received broad-beam radiation at doses of 6, 12, or 18 Gy. The final group of duck eggs received no radiation. After hatching, the ducks were followed for the development of ataxia (general weakness and lameness), and their brains were examined for signs of damage.
In the embryos treated with microbeam radiation -- except for the high-dose control group, which suffered terrible damage -- most of the ducks in the other dose groups developed normally with no ataxia, and showed no brain damage during histological studies. In the 18 Gy broad-beam group, on the other hand, all the ducks developed ataxia before 90 days of age.
"This shows that the ducks' brains were about ten times more tolerant to the microbeam radiation than the broad beams," Dilmanian says. "Even when the unirradiated areas between the microbeam slices are taken into account [i.e., when the dose is averaged over the entire area treated], microbeams still have an approximately three-fold advantage over broad-beams in terms of normal brain tissue tolerance," he says.
Previous experiments have shown that these same microbeam doses can destroy or slow the growth of malignant brain tumors in rats. Furthermore, in those studies, the treatment was accomplished by irradiating the tumors from only one direction and in one treatment. This is in contrast to conventional radiation treatment, which is carried out from different angles and over as many as 40 sessions.
The scientists hypothesize that, in MRT, some of the endothelial cells (cells that line blood capillaries) survive in the interbeam regions. In normal tissue, these cells appear to replace the neighboring cells killed by the beam. But in tumors, this replacement process may be impaired, so the blood flow stops and the tumor is destroyed.
The next step will be to compare the highest dose that can be tolerated before normal tissue is harmed with the lowest dose needed to destroy tumors. If it can be established that normal tissues tolerate microbeam doses above what is needed to destroy tumors -- i.e., if the ratio of these doses is higher than that for conventional broad-beam radiation, which is close to one -- then MRT would be one step closer to human trials.
This research was funded by the U.S. Department of Energy, which supports basic research in a variety of scientific fields, and the Children’s Brain Tumor Foundation.
The U.S. Department of Energy's Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies. Brookhaven also builds and operates major facilities available to university, industrial, and government scientists. The Laboratory is managed by Brookhaven Science Associates, a limited liability company founded by Stony Brook University and Battelle, a nonprofit applied science and technology organization.
Note to local editors: Avraham Dilmanian lives in Yaphank, New York.
Journal
Cellular and Molecular Biology