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Suicidal cells respond better to chemo

Dividing cells Researchers have found that cancer cells on the brink of suicide respond to chemotherapy much better than others.

The results could also explain why normal cells are less affected by chemotherapy drugs than cancer cells, which has been a mystery even though chemotherapy has been used widely for 60 years.

Dr Anthony Letai at the Dana-Farber Cancer Institute in Boston, USA, and colleagues report their work in this week's edition of Science .

It is thought that traditional chemotherapy drugs act on rapidly dividing cells. This is why they affect cancer cells, which divide frequently, and damage normal (but rapidly dividing) cells such as those found in hair follicles, the gut lining and bone marrow causing side effects such as hair loss, diarrhoea, and reduced immune response.

But this is far from the whole story. Although cell proliferation is important, some rapidly dividing tumours are resistant to chemotherapy, yet other slower growing ones can respond well to it.

Indeed, Letai wonders why chemotherapy ever works at all, without killing all the body's cells.

"The [chemo] drugs that we use target DNA and microtubules, and every single cell in the whole body has those," he says, adding that there must be reasons why chemo tends to spare normal cells and works better on some cancers than others.

Cell suicide

The researchers hypothesise that the state of the cancer cell's powerhouse — the mitochondria — may be the key. Mitochondria not only provide the energy for the cell to live, they decide whether a cell lives or kills itself.

"It has been appreciated for quite a while that the mitochondria are very important in integrating a lot of the signals in the cell and making the decision whether the cell decides to commit suicide or stay alive", says Letai.

All cells are programmed to kill themselves if they become too damaged, explains Letai. This includes cancer cells, which accumulate damage because they are growing too quickly, in the wrong place and in the wrong way.

To test their theory, Letai's group looked at cancer cells from 85 patients, covering four different types of cancer. They used a test they had previously developed called 'BH3 profiling' which tells them how close the mitochondria are to the point of triggering cell death.

The team found that patients with cancer cells containing mitochondria which were close to initiating cell suicide, were much more likely to respond well to conventional chemotherapy. This effect was seen in all four cancers: two types of leukaemia, multiple myeloma (a bone marrow cancer) and ovarian cancer.

Letai sees these cancer cells as "being on the edge of a precipice". It seems the chemotherapy tips them over into cell death.

The team also found that mitochondria in normal cells from both mice and humans showed up on their test as being less "primed for cell death" than most cancer cells, which fits with chemotherapy being less damaging to normal tissue.

Personalised treatment

Letai hopes the team's research will lead to the ability to test cancer cells from a patient to see whether they are likely to respond well to chemotherapy.

Professor Andrew Roberts of the Walter and Eliza Hall Institute for Medical Research in Melbourne endorses the idea that cell suicide is important in chemotherapy, and says the research is most valuable in understanding the biology involved.

But he is cautious about the scope for personalised cancer therapy in the near future, saying that more work needs to be done.

"Biological processes are spectra — they are not 'yes' or 'no'. Yet patients want answers in black and white - not grey. Can I take these results and predict how an individual patient will go with certainty? No. But it is definitely a step in the right direction."