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Mouse Drug May Mean Safer Chemotherapy

10 September 1999 7:00 pm
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A novel compound may one day help alleviate side effects of harsh cancer treatments for some people. In today's Science, researchers report that a small organic chemical protects mice against lethal radiation doses.

Chemotherapy and radiation don't just kill tumor cells, they also damage healthy tissues and cause anemia, infections, vomiting, diarrhea, and other problems. These side effects can be so severe that they prevent patients from receiving effective treatment. Although some compounds help protect healthy tissue from cancer therapies, they have only limited effects, such as helping restore the bone marrow's ability to make red blood cells.

Now, by capitalizing on their knowledge of p53, a powerful tumor suppressor gene, a team led by Andrei Gudkov of the University of Illinois, Chicago, may have found a better way to ease side effects in some patients. Earlier results had shown, for example, that the healthy tissues of normal mice suffer more from gamma irradiation than do the healthy tissues of p53-deficient mice. That meant that blocking p53 could potentially prevent side effects--but only if it could be done without triggering the formation of additional tumors.

The team devised a cultured cell system they could use to screen rapidly for compounds that block this activation. And out of 10,000 synthetic chemicals, one looked particularly promising: pifithrin-a (PFTa). It blocked cell suicide triggered by radiation as well as by four chemotherapeutic drugs, and it also inhibited growth arrest induced by radiation. "Amazingly," says Gudkov, "a single injection rescued [normal] mice completely" from a radiation dose that usually kills 60% of the animals, while having no effect on p53-deficient animals. What's more, the treated mice have survived more than 8 months--about half the normal mouse life-span--and none have developed any tumors.

Before any such compound can be used in the clinic, more long-term animal studies are needed to make sure that the drugs don't induce tumor formation or have other dangerous side effects, warns medical oncologist Ronald Bukowski, director of experimental therapeutics at the Cleveland Clinic. And people whose tumors contain an active p53 gene--true for 50% of cancers--won't be eligible for the drug, because it could help their tumors fight the therapy. But if the new compounds pan out in humans, it would be great news for cancer patients.

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