Damage to the gastrointestinal tract, lung and brain has long been the dose-limiting factor for chemotherapy and radiation therapy. But until now, scientists did not know which cells targeted within those organs were responsible for the lethal responses. Researchers at Memorial Sloan-Kettering Cancer Center have discovered that, in mice, destruction of endothelial cells that line small blood vessels is the cause of the tissue damage and death that results from radiation therapy and possibly chemotherapy.
These researchers have developed pharmacologic and genetic interventions that prevent endothelial apoptosis (programmed cell death) and gastrointestinal damage in mice.
Their findings, published in the July 13 issue of Science, have implications for understanding how radiation affects normal organs and tumors, and may provide a new approach for targeting and destroying tumors more effectively.
"This research is an example of how new biology improves our ability to provide better treatment," said radiation oncologist Zvi Fuks, M.D., study co-author and Deputy Physician in Chief for Planning at Memorial Sloan-Kettering. "It combines biochemistry, cell biology, genetics, and pharmacology and provides a model in which the details of an important mechanism are understood. The promise of the research is that it gives us an approach to interfere with cellular events in a targeted way."
GI tract damage is a limiting factor in how intense radiation and chemotherapy treatments can be. At high doses, these treatments cause side effects such as diarrhea and infection, which can be fatal.
It was previously assumed that the cells damaged by cancer therapies were the stem cells in the GI tissue. But in the current experiment, researchers found that the blood vessels are actually the target.
The researchers also showed that by blocking a cell-signaling pathway called the acid sphingomyelinase pathway -- either by a gene mutation or a drug called basic fibroblast growth factor -- damage to the GI tract in mice could be prevented.
This pathway was already known to be involved in apoptosis of the microvascular endothelium cells. In the current paper, researchers have now demonstrated that by blocking this pathway, mice can be given higher doses of radiation therapy with no gastrointestinal damage.
This finding eventually could be applicable for human cancers, especially those that are treated with abdominal radiation therapy such as gastrointestinal, genitourinary and gynecological tumors.
"The question we need to ask is whether we will be able to use this new knowledge to protect the blood vessels of healthy tissue or to more effectively target the blood vessels of tumor tissue," said Richard Kolesnick, M.D., senior author of the paper and head of the Signal Transduction Laboratory at Memorial Sloan-Kettering.
Although so far the researchers have shown that microvascular endothelial cells are targeted in healthy tissue, it is presumed that the same therapies will target the blood vessels in tumors.
"Tissue is tissue," said Dr. Kolesnick. "Although tumor tissue is not normal, the blood vessels that supply them are the same."
Other MSK researchers involved in the work are first author Francois Paris, Ph.D.; Anthony Kang, Ph.D.; Paola Capodieci, Ph.D.; Gloria Juan, Ph.D.; Desiree Ehleiter, B.A.; Adriana Haimovitz-Friedman, Ph.D.; and Carlos Cordon-Cardo, M.D., Ph.D. The research was funded by the National Institutes of Health and the National Cancer Institute.
Memorial Sloan-Kettering Cancer Center is the world's oldest and largest institution devoted to prevention, patient care, research and education in cancer. - By Joanne Nicholas
[Contact: Joanne Nicholas ]
16-Jul-2001
