July 12, 2001
Study Suggests Way to Fight Radiation Side Effect
By Merritt McKinney

NEW YORK (Reuters Health) - In an unexpected finding, experiments in mice show that the toxic gastrointestinal side effects of radiation therapy are caused by damage to the cells lining tiny blood vessels in the gut.

But treatment with a growth factor blocked the harmful effects in mice, suggesting a potential way to prevent the side effects in people undergoing radiation therapy for cancer, New York researchers report in the July 13th issue of Science.

Radiation therapy can destroy cancer cells, but the treatment can also wreak havoc on the gastrointestinal tract, leading to diarrhea, dehydration, infections and even death. Experts have long thought that the symptoms were caused by damage to stem cells in intestinal glands called crypts.

But a team at Memorial Sloan-Kettering Cancer Center has found that, in mice at least, a single dose of radiation causes cells lining tiny blood vessels in the intestine to commit suicide. According to Dr. Richard Kolesnick and colleagues, the death of these cells probably triggers the damage to stem cells in the intestinal crypts.

This research represents ``an example of the new biology,'' Kolesnick told Reuters Health in an interview. This means that rather than looking at radiation damage on the cellular level, ''we are starting to ask how tissues work,'' he said.

Kolesnick and his colleagues have been trying to figure out ''which components of the tissue are the components that respond to damage and are critical to the protection of the tissue.''

These new findings suggest that the gastrointestinal side effects of radiation are ``in fact mediated not by direct damage to critical stem cells, but indirectly by damage to blood cells,'' Kolesnick explained.

Moreover, now that researchers have a better idea of how radiation damages tissue, it may be possible to block this damage, the report indicates. Treating mice with a substance called bFGF, or basic fibroblast growth factor, blocked the damage to the blood vessel cells in the animals' guts.

The investigators were also able to block the destruction in the gut by manipulating the genes of the mice. In mice that had the gene for acid sphingomyelinase--an enzyme found in cells lining vessels and tissues that is involved in the cell-death process--radiation did not cause widespread destruction in the cells of the blood vessels.

In an interview with Reuters Health, study co-author Dr. Zvi Fuks said the research suggests it may be possible to manipulate the response of tissue to radiation. He explained that tumors have a range of responses to radiation. Until now, it has been a ``near mission impossible'' to identify which response is the prevailing one, he said.

If the findings are confirmed in humans, however, ``then we significantly improve the ability to design methods of controlling the response,'' Fuks said.

But the researcher stressed that it is too early to know whether the approach will be effective in people. ``There is a lot more work that needs to be done,'' he said.

Besides its implications for reducing the side effects of radiation treatment, this research could also be relevant to therapies that aim to cut off the blood supply to tumors, according to two Boston researchers.

The study ``prepares the way'' for studying the effects of radiation on the cells lining tiny blood vessels, Dr. Judah Folkman, of Children's Hospital, and Dr. Kevin Camphausen, of Harvard Medical School (news - web sites), state in an editorial that accompanies the report.

The editorialists suggest that it may be possible to make tumors more sensitive to the effects of radiation by first treating them with so-called anti-angiogenic therapy, which aims to prevent tumors from growing new blood vessels. Then it may be possible to destroy tumors using lower doses of radiation, Folkman and Camphausen note.

SOURCE: Science 2001;293:293-297.


The gut collects radiation free radicals from over the volume of the gut's cross section, which means the dose to these cells is higher than other cells in the body.

 The mechanism killing the cells is likely free radical damage to the mitochondria of cells leading to cell death.