Blocking VEGF can enhance radiation therapy

July 14, 1999

Blocking the action of vascular endothelial cell growth factor (VEGF), a substance that encourages the growth of new blood vessels, can dramatically increase the anti-tumor effects of radiation therapy according to medical researchers from the University of Chicago and Harvard medical schools in the July 15, 1999 issue of Cancer Research.

This report adds to the mounting enthusiasm for combining drugs that prevent the growth of new vessels--such as angiostatin, endostatin, and now anti-VEGF--with other forms of cancer therapy.

"Despite all the media attention devoted to angiostatin and similar agents, most scientists suspect it's unlikely that, by themselves, these new drugs will have a very dramatic effect on most types of cancer," said Ralph Weichselbaum, MD, professor and chairman of radiation oncology at the University of Chicago and director of the study.

"But we have long been certain," he added, "that radiation therapy works quite well for eradicating relatively small human tumors. Now we have good reasons to believe that combining radiation with angiogenesis inhibitors can make this well established treatment significantly more effective, perhaps even against comparatively large tumors, with very little added toxicity."

Angiostatin and endostatin provide a big boost to radiation therapy, Weichselbaum's group has shown in studies done with mice, but neither drug has begun the first phase of human testing. In this Cancer Research paper, Weichselbaum and colleagues demonstrate that anti-VEGF, which is already in phase-II clinical trials, can have an equally dramatic impact.

The researchers' interest in vascular endothelial cell growth factor was piqued by their discovery that tumors produce three-to-six times more VEGF after exposure to radiation, and these elevated levels persist for up to two weeks. By speeding the growth of new blood vessels to supply the radiation-damaged tumor, VEGF helps the cancer bounce back from radiation therapy, contributing to a tumor's ability to resist this form of treatment.

So Weichselbaum's team compared the anti-tumor effects of anti-VEGF alone, radiation alone and the two in combination on mice with several different types of cancer.

In all four tumor types studied--Lewis lung carcinoma, human squamous cell carcinoma, human esophageal adenocarcinoma, and a glioblastoma--the combined therapy was much more effective than either anti-VEGF or radiation therapy alone.

"The anti-tumor effects were greater than additive," note the authors. "Even a slight inhibition of VEGF action can result in a marked increase in the anti-tumor effect of ionizing radiation."

For example, giving mice with Lewis lung carcinoma a small dose of anti-VEGF reduced tumor size by 42.6 percent. Treatment with low doses of radiation alone reduced tumor size by 43 percent. But treatment with low doses of anti-VEGF and radiation resulted in reduction of tumor size by 78 percent.

Combined treatment also slowed re-growth of these rapidly expanding tumors. It took untreated Lewis lung carcinoma tumors only 2.6 days to double their original volume. Tumors treated with anti-VEGF required 3.4 days. Tumors treated with radiation therapy took four days, but those treated with radiation and anti-VEGF took nine days.

To uncover how the combination altered tumor growth, the researchers exposed human tumor cells and blood vessel cells in the test tube to VEGF, anti-VEGF, and radiation. Neither VEGF nor anti-VEGF affected tumor cells, but adding VEGF protected blood vessel cells from radiation and adding anti-VEGF made blood vessel cells more susceptible to radiation.

"The combination of anti-VEGF and radiation therapy was much more effective than we might have expected," said Weichselbaum. Removing VEGF "not only slowed tumor recovery from treatment, it actually appeared to make existing tumor blood vessels more susceptible to radiation damage," he added. "Anything we can do to tip the balance in favor of the patient and against the tumor has the potential to make an established cancer therapy that much more valuable."

Additional authors of the paper include: David Gorski, Michael Beckett, Nora Jaskowiak, Douglas Calvin, Helena Mauceri, Rabih Salloum, Saraswathy Seetharam, Ann Koons, and Danielle Hari, from the University of Chicago, and Donald Kufe from Harvard. Funding support came from the National Cancer Institute, the Lederer Foundation, the Center for Radiation Therapy and the Geraldi-Norton Foundation.

Summary:
VEGF encourages the growth of new blood vessels. Tumors produce VEGF after exposure to radiation. An antibody that blocks VEGF increases the anti-tumor effects of radiation therapy. Anti-VEGF increases cell killing by ionizing radiation, makes blood vessel cells more susceptible to radiation therapy and inhibits tumor recovery.

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