Angiostatin to enhance radiation therapy

Best use of angiostatin may be to enhance radiation therapy

December 14, 1998

The team of scientists who discovered that angiostatin could dramatically boost the effects of radiation therapy has now shown that only brief exposure to angiostatin is required to get most of the drug's radiation-boosting anti-tumor effects. Without concomitant radiation therapy, additional exposure to low doses of this highly touted, costly and hard-to-obtain protein did not enhance treatment.

This latest report, by researchers from the University of Chicago Medical Center, Harvard Medical School, and Northwestern University in the December 15, 1998 issue of Cancer Research, adds to the mounting enthusiasm about combining angiostatin with other forms of cancer therapy.

"The limited angiostatin supplies may be most effectively and efficiently used in combination with cytotoxic therapies such as ionizing radiation," note the authors. "These results suggest a new approach to the design of clinical trials with angiostatin and other anti-angiogenic agents."

The research team, led by Ralph Weichselbaum, MD, professor and chairman of radiation oncology at the University of Chicago, tested the anti-tumor effects of angiostatin and radiation alone and in various combinations. They used large (500mm3), rapidly growing human tumors transplanted into mice.

As expected, the most effective therapy was the combination of simultaneous angiostatin and radiation therapy. What was not anticipated was how little angiostatin was required to make a big difference, or how limited the benefits would be from continuing to give low-dose angiostatin after completing a short course of radiation.

The study wasn't designed to assess the effects of angiostatin, used here in very small doses, but to determine the most effective and efficient ways to combine it with radiation therapy.

The research involved six groups of mice. One group received no treatment, one got angiostatin alone, and one group received radiation therapy.

Mice in the other three groups received different combinations of angiostatin and radiation. One group received angiostatin and radiation together for two days. One group received radiation for two days followed by angiostatin on days two through 14. One group received both radiation and angiostatin for the first two days, followed by angiostatin on days two through 14.

When their tumors were measured at day nine, and again at day 14, the mice that received both angiostatin and radiation together had the smallest tumors. Angiostatin dramatically improved the effects of radiation therapy if given at the same time, but at these low doses had little effect when given without same-day radiation therapy.

"This study extends our previous finding that angiostatin becomes much more effective when used to enhance the effects of radiation," said Weichselbaum, "and that radiation, already a standard of cancer therapy, could become more effective with a boost from short courses of concomitant low-dose angiostatin. This combination may be the most efficient, most beneficial use of this agent, which is in extremely short supply."

Angiogenesis inhibitors could make radiation much more effective at providing local control of cancer, Weichselbaum suggests. "Local control is a crucial part of treatment for many tumors, including prostate, brain, head and neck, and other cancers," he added. "It could even expand the use of radiation therapy to some forms of metastatic disease without requiring high doses."

Additional authors of the paper include David Gorski, Helena Mauceri, Rabih Salloum, Michael Beckett, and Samuel Hellman from the University of Chicago; Vikas Sukhatme and Donald Kufe from Harvard; and Stephen Gately and Gerald Soff from Northwestern. Funding support came from the National Institutes of Health.

Summary:
The scientists who discovered how low-dose angiostatin enhances radiation therapy demonstrate that only brief exposure to angiostatin is required to get substantial anti-tumor effects. Additional exposure at low doses did not increase anti-tumor effects. This report adds to the mounting enthusiasm for combining angiostatin with radiation therapy.

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