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'Guardian gene' may hinder some cancer treatments

May 16, 2007 By Erika Check This article courtesy of Nature News.

But having a mutated gene may help ward off tumours after chemotherapy.

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A key gene that helps the body to avoid cancer may sometimes hinder cancer treatment, suggest scientists today. On the flipside, the mutated version of the gene, which usually cannot protect against cancer, might work to a patient's advantage during therapy.

Researchers have found that some cancer patients with defective versions of the p53 gene lived longer after drug treatment than patients with normal versions of the gene. The results are surprising, because the p53 protein is a so-called 'tumour suppressor' that induces suicide in damaged cells, thereby preventing them from seeding new cancers. This is thought to help the body deliver a knockout blow to cancer cells that are weakened by chemotherapy. But the new study hints that, in some circumstances, p53 may hurt more than it helps.

Other scientists say the new study is provocative, but caution that on its own it does not prove the suggestion. It fails to pass a critical statistical test and does not definitively show that p53 is the culprit in the patients who fared worse, notes Anton Berns, a cancer geneticist at The Netherlands Cancer Institute in Amsterdam. But, he adds, the study is intriguing and should spark further investigation, because it points in the same direction as other recent work that suggests a complex role for p53 in chemotherapy.

"This study should be an additional encouragement to test this possibility more thoroughly," says Berns.

For better or for worse

P53 may be a double-edged sword.
John McDonald, the Georgia Institute of Technology.
Researchers led by John McDonald of the Georgia Institute of Technology in Atlanta examined 43 ovarian cancer tumours that were surgically removed from women. Some of the tumours were malignant, meaning they could invade other tissues. To shrink these malignant tumours, doctors had hit them with a dose of chemotherapy before the surgery.

McDonald's team analysed the tumours, and found that some of the malignant tumours had intact p53 genes, whereas others had mutated, probably-useless p53 genes. They presumed that the patients with intact versions would have fared better after surgery, because their p53 proteins would hit the self-destruct button in lingering cancer cells. But they found just the opposite: patients in the second group were more likely to survive for five years after surgery.

McDonald points out that p53 doesn't just spur cell suicide — it also helps cells to repair genetic damage. So it's possible, he says, that the intact p53 genes repair cancerous cells that are injured by chemotherapy, allowing them to regrow into tumours after surgery.

"p53 may be a double-edged sword," McDonald says. His team is following up by studying p53 in mouse models of chemotherapy.

One way or another

But for now, McDonald's hypothesis is a long shot. There were not many patients in this study, and those with mutated p53 may have lived longer simply because of chance. So McDonald's hypothesis may not be correct.

But McDonald and Berns agree that it is worth following up on the study, because other recent papers also suggest that temporarily disabling p53 may actually help patients undergoing chemotherapy or radiation (see 'Tuning the body's defence to cancer').

These studies conflict with other reports that p53 is essential for patients' response to chemotherapy, so teasing apart p53's myriad roles will be no easy task.

References

  1. Moreno C. S., et al. PLoS ONE, (2007).

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