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"Tumor hypoxia has become a major target in solid tumors," says Giovanni Melillo, M.D., of NCI's Developmental Therapeutics Program and SAIC-Frederick, Inc. "When cells lack oxygen - hypoxia -, the first thing they do is compensate, try to make new blood vessels. It's good for the tumor, bad for the patient. The cancer becomes more aggressive."
A transcription factor called HIF-1 (hypoxia-inducible factor) is essential for angiogenesis, the growth of new blood vessels. To find drugs that would block HIF-1, and ultimately starve tumors, Melillo and colleagues designed an assay and used it to screen one of NCI's chemical libraries. The high throughput screen uses automated equipment to screen thousands of compounds in a day.
They identified several potentially active compounds, some of which are already approved cancer drugs. Based on their research, however, those drugs would be used in a different way. Most anticancer drugs are given at high doses in cycles, one or a few days of drug followed by a three-week break, to let the bone marrow and other healthy cells recover. To disable HIF-1, a lower, daily dose would likely be more appropriate.
The researchers are studying these drugs in animals, to see if a low, continuous dose could sustain inhibition of HIF-1 while avoiding the harmful toxicities of standard chemotherapy.
Melillo says he hopes one day to see these drugs used in combination with drugs that block angiogenesis. "If one is able to shut down the blood supply to the tumor, the tumor - lacking oxygen - activates the HIF-1 response to survive," he explains. "If a second drug can block this compensatory response, the effect against the cancer cells can be much more pronounced. We'll be shutting down
a response essential for cancer cells to survive."
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