This study appears in the 16 May 2003 issue of the journal Science, published by the American Association for the Advancement of Science.
The researchers pinned down this lesser-known therapeutic result of radiation therapy by genetically inactivating an enzyme, "acid sphingomyelinase." Tumors growing in mice without this enzyme were radioresistant and did not shrink after being hit with low doses of radiation. The same tumors growing in mice that had the enzyme displayed the expected degree of tumor control.
"People assumed that damage to the DNA in the nuclei of tumor cells was the only way that radiation killed tumor cells. Our work shows that there is another radiation-induced pathway initiated when radiation strikes endothelial cells," said Richard Kolesnick who is a practicing physician and author on the paper from the Memorial Sloan-Kettering Cancer Center in New York City.
"We found that acid sphingomyelinase is necessary for programmed cell death, or "apoptosis" of endothelial cells. When the endothelium contained the enzyme, the tumor was radiosensitive. In contrast, when the endothelium lacked the enzyme, tumors became radioresistant," said Kolesnick.
The research group studies tumors in the context of their microenvironments which include the endothelial cells. With this approach, the interactions between tumor microvessels and the tumor cells can be observed.
The endothelial cells are recruited from the host to form the blood vessels required to provide oxygen and nutrients to the tumor. The development of new blood vessels is called angiogenesis.
"When the angiogenic blood vessels are damaged, the death of tumor cells results," said Kolesnick.
To date, most radiation therapy research and clinical regimens have targeted the tumor cells themselves. However, the authors say that the field is ready for a paradigm shift that broadens the scope of the impact of radiation therapy to include the microvasculature.
"This research provides a new dimension to solid-tumor therapy. There will have to be clinical approaches that combine anti-angiogenic therapy with radiation," said Zvi Fuks, a practicing radiation oncologist and co-investigator from the Memorial Sloan-Kettering Cancer Center.
Fuks explained that these findings demonstrate that there may be new ways to make tumors more susceptible to radiation.
"The ability to 'de-protect' the vasculature will provide new targets for tumor therapy. Advances in tumor biology will sharpen the focus of clinical treatments and provide much needed scientific background for new approaches to cancer therapy," said Fuks.
The authors explained that they are part of a small but growing group who support new approaches to radiation therapy for cancer treatment.
"Judah Folkman has been suggesting this for many years," said Fuks. (See the Perspective article by Judah Folkman and Kevin Camphausen. Science 2001 July 13; 293: 227-228)
"We now have the data to translate this hypothesis into a useful therapeutic approach," said Fuks, who reflected on the history of radiation therapy.
"In 45 years, we have failed in finding a drug that will make tumor cells more sensitive to radiation. We find things that work in a petri dish. But when you go to patients, they don't work" Fuks said.
"We need to understand, at the therapeutic dose range, the unique roles that the microenvironment and tumor cell components play in the overall response of the tumor to radiation to maximize the value of such treatments," said Fuks.
Monica Garcia-Barros, Francois Paris, Carlos Cordon-Cardo, David Lyden, Adriana Haimovitz-Friedman, Zvi Fuks and Richard Kolesnick are from Memorial Sloan-Kettering Cancer Center in New York, NY. Shahin Rafii is from Cornell U. Medical College in New York, NY.
Funding for this research was provided in part by the National Institutes of Health, the American Cancer Society, and the Doris Duke Charitable Foundation
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