Adding low doses of angiostatin--a naturally produced substance that
inhibits angiogenesis--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 16th 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
Angiostatin Dramatically Improves Results of Radiation
"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,MD, 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 and 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 and 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
(SQ2O-B), angiostatin alone reduced the tumor volume by 16% and
radiation alone reduced volume by 18%, but combined therapy reduced
the average tumor volume by 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 looking at the effects of
each treatment on the cells that line arteries and veins, however,
they found that angiostatin not only killed some of these endothelial
cells but also sensitized the surviving cells to radiation.
Therefore, the radiation, in combination with angiostatin, enhanced
the drugs ability to block the growth of new tumor-supplying
"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
Low Angiostatin Doses Needed
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, Kern 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.