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【bio-news】Tuning the body's defence to cancer

Tuning the body's defence to cancer
Turning off our natural killer could help to reduce chemotherapy side effects.
Lucy Heady
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.
当细胞受到一定剂量的辐射作用而使其DNA受到严重伤害时,p53就开始发挥作用。一般10亿个损坏细胞中只包含一个可能导致癌症的突变体,但是p53会杀伤所有缺陷细胞。研究的领导者,sanfrancisco 加利福利亚大学的gerard evan说:“这就好象为了防止***者的出现而杀掉所用的嫌疑犯“。这种“不分青红皂白”的攻击导致了接受放射治疗和化疗的病人出现脱发以及严重呕吐等症状。

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.

未完待续 Switched on
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.


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作者:admin@医学,生命科学    2011-09-01 05:13