July 20, 1998 Adding low doses of angiostatin -- a naturally produced substance that inhibits the formation of new blood vessels -- to standard radiation therapy dramatically improves the response to cancer treatment in animal models without increasing toxicity, report researchers from the University of Chicago Medical Center, Harvard Medical School and Northwestern University in the July 16 issue of Nature.
Human angiostatin alone produced only a modest decrease in tumor growth when given to mice with large tumors. Radiation therapy alone produced a slightly greater response. The combination of angiostatin and radiation, however, caused significant growth inhibition, demonstrating a powerful synergistic effect, even in mice with very large tumors.
"Our finding suggests that radiation therapy, already a standard of cancer care, could be dramatically improved by simultaneous administration of relatively small doses of angiostatin," said Ralph Weichselbaum, M.D., professor and chairman of radiation oncology at the University of Chicago and director of the study.
"This combination could make radiation much more effective at providing local control of cancer, a crucial part of treatment for many tumors, including prostate, brain, head & neck and other cancers. It could even expand the use of radiation therapy to some forms of metastatic disease without requiring high doses."
The researchers also studied the combination of radiation plus mouse angiostatin against human cancers of the brain, head & neck, and prostate that had been transplanted into mice. Once again, the combination was far more effective than the combined effects of each therapy used alone.
For example, in mice with large radiation-resistant human tumors (SQ20-B, a form of head & neck cancer), angiostatin alone reduced the tumor volume 16%, radiation alone reduced volume 18%, but combined therapy reduced the average tumor volume 64%.
Surprisingly, tumors treated with the combined therapy had fewer blood vessels than those treated with angiostatin alone. Radiation kills tumor cells but was not expected to alter tumor blood-vessel formation. Angiostatin inhibits the growth of new blood vessels but has no effect on tumor cells.
When the team performed additional studies, however, looking at the effects of each treatment on the cells that line arteries and veins, they found that angiostatin not only killed some of these endothelial cells, but it also sensitized the survivors to radiation. So the radiation, in combination with angiostatin, enhanced the drug's ability to block the growth of new tumor-supplying blood vessels.
"We were particularly pleased by the manner in which these two agents team up to shrink tumors," said Weichselbaum. Although cancer cells mutate frequently, enabling them to build up radiation resistance, the vessels that feed these tumors are genetically stable and therefore far less likely to develop resistance.
"Angiostatin brings radiation into action against the tumor vasculature in addition to its impact on tumor cells," said Weichselbaum, "which means that resistance is far less likely to develop. This suggests that the combination of treatments may be effective against tumors that were not previously susceptible to radiation therapy."
The researchers were also excited by the remarkably low doses of angiostatin required to have an impact, when combined with radiation -- far less than the effective doses of the drug when used alone.
Since angiostatin is currently in extremely short supply, "clinical trials of low doses used briefly along with radiation to eliminate tumors, rather than higher doses given over sustained periods to prevent new growth, are perhaps the logical next step," advised Weichselbaum.
Additional authors of the paper include Helena Mauceri, Nader Hanna, Michael Beckett, David Gorski, Mary-Jane Staba, Kerri Stellato, Kevin Bigelow and Ruth Heimann from the University of Chicago; Stephen Gately and Gerald Soff from Northwestern; and Mohanraj Dhanabal, Vikas Sukhatme, and Donald Kufe from Harvard.
Funding support came from the National Institutes of Health.
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