Radiation harms blood vessels before gut.

When physicians aim radiation at a tumor in the pancreas or irradiate the entire body of someone with leukemia, the therapy can devastate the stomach and abdomen. Nausea, diarrhea, infections, and even death may result.

These responses occur because the radiation wipes out the linings of the stomach and intestines. But how? Most investigators argue that radiation directly kills epithelial stem cells, which normally produce the cellular linings. Other scientists challenge that view, contending that the radiation destroys blood vessels that sustain the stem cells, indirectly affecting the lining.

New studies of irradiated mice support this indirect pathway, say Zvi Fuks and his colleagues at Memorial Sloan-Kettering Cancer Center in New York. They further suggest in the July 13 SCIENCE that their work may someday lead to drugs that make radiation therapy safer.

The findings support "a whole new paradigm on how radiation may affect tissue," says Fuks. "We are shifting the focus to the integrity of the blood vessels."

After their earlier studies in mice had indicated that radiation targets the tiny blood vessels, or capillaries, of the brain and lungs, Fuks and his colleagues turned to the gastrointestinal tract. In this region also, mouse endothelial cells that make up the capillaries begin to commit suicide soon after radiation exposure, the researchers found.

They next tested mice with a mutation that prevents endothelial cells from committing suicide. When irradiated at doses that cause normal mice to die from gastrointestinal problems in about a week, the mutant mice survived a few days longer, until they died from bone marrow failure.

The scientists also found that administering a protein called basic fibroblast growth factor (bFGF) to normal mice protected the animals from the abdominal side effects of radiation therapy. This protein interacts with endothelial cells but not with gastrointestinal stem cells, study coauthor Richard Kolesnick notes.

Catherine Booth of EpiStem in Manchester, England, remains unconvinced that the death of endothelial cells kills the gut's stem cells. "The causal relationship is very weak," she says.

Radiation oncologist Paul Okunieff of the University of Rochester (N.Y.) Medical Center concurs and notes that radiation probably targets both endothelial and epithelial cells directly.

Still, Booth and Okunieff agree that treatments with cell-protecting proteins such as bFGF may increase the dose of tumor-killing radiation that a patient can tolerate. Biotech firms have already begun testing this strategy on cancer patients, Booth notes.