Tuning the body's defense to cancer
Turning off our natural killer could help to reduce chemotherapy side effects.
A fundamental shift in our understanding of the body's natural defence mechanism against cancer has revealed an odd trick: turning this weapon off during chemotherapy might actively help to reduce side effects such as hair loss.
Our cells contain a protein called p53, dubbed 'the guardian of the genome', which regulates the process of DNA replication. It also plays a crucial role in cancer: 50% of human tumours contain a mutation or a deletion in the gene that makes p53.
p53 does two things: it repairs broken or damaged strands of DNA, and kills off cells containing defective DNA. Both can help to fight against cancer. But the latter can also have negative effects.
When cells suffer massive DNA damage, from a dose of radiation, for example, p53 steps into enthusiastic action. Only about one in a billion damaged cells will contain a mutation likely to cause cancer, but p53 will kill off all damaged cells. "It's like preventing the rise of a potential dictator in a country by killing off the whole population," says Gerard Evan of the University of California, San Francisco, who led the research. This indiscriminate destruction causes the hair loss and extreme nausea experienced by radio- and chemotherapy patients.
The two actions of p53 were thought to be intimately linked, making this overkill an unfortunate but necessary part of how p53 stops the formation of tumours. The results from Evan's lab, however, tell a different story.
Evan's group developed a pioneering mouse method to try to unlock the function of p53. In this method the gene is not deleted, as in traditional 'knockout' experiments, but is instead mutated so that it can be switched on or off at any stage by injecting the mice with a simple chemical.
Three sets of these 'knockin' mice, all with a switchable p53 gene, were blasted with high-intensity radiation similar to that experienced by radiotherapy patients. This causes extensive DNA damage, as well as a type of cancer known as lymphoma.
Mice that had p53 switched on during the radiation, but turned off immediately afterwards, fared the worst. They suffered massive tissue damage as the p53 responded to DNA damage by killing off cells. And they still formed tumours and died from cancer, to the same extent as mice who had p53 turned off for the entire procedure: mice in both groups lived for a maximum of 300 days.
Mice that had p53 turned off during the irradiation, and turned on 8 days after the radiation blast, suffered least. They had no detectable tissue damage, and a vastly reduced number of lymphomas they lived an average 99 days longer than the other mice. Mice with p53 turned on for the entire procedure as is the case with human patients suffered tissue damage but were spared from extensive lymphomas. Although it is impossible to turn genes on and off perfectly with this technique, Evan notes, the data in this case are very clear. They report the results in Nature1.
The results imply that the two actions of p53 must be spurred by independent mechanisms, says Evan. The key to p53's tumour-suppressing role seems to be another protein known to be involved with cancer, called p19ARF, which is only produced in those one in a billion cells that suffer a cancer-causing mutation. Evan and his team showed that mice lacking one of either of these proteins formed deadly lymphomas: only mice with both could fight off the tumours. It seems that p19ARF activates p53, they say, which in turn causes the tumorous cells to selectively die.
The importance of these results for cancer sufferers is clear, says Evan: suppressing p53 temporarily during chemo and radiotherapy should allow us to diminish the nasty side effects, while still offering the body protection from tumours. Andrei Gudkov at the Lerner Research Institute in Cleveland, Ohio, and his colleagues are developing drugs that act as p53 inhibitors; these have shown protection against tissue damage in trials with mice.
There are many hurdles in the way of treatment for humans, however. Proteins known to play a role in cancer may behave differently in mice and people, for example. Lisa Wiesmueller of the University of Ulm, Germany, notes that mice develop lymphomas when exposed to high doses of radiation whereas humans often develop breast cancer; it is possible that p53 will suppress different tumours in different ways, she says.
To try and complete the story, Evan's group is currently working on using the same 'knockin' approach on mice with different kinds of cancer.
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- Christophorou M. A., Ringshausen I., Finch A. J., Brown Swigart L.& Evan G. I.Nature, advanced online publication, (2006). DOI: 10.1038/nature05077 (2006).