BBC Monday, 16 July, 2001, 00:07 GMT 01:07 UK Scientists disable cancer's defences

Scientists have discovered a way to render cancer cells defenceless to chemotherapy.

Cancers are often sensitive to chemotherapy at first, but over time many build up resistance.

A team from Glasgow University has discovered that this defence mechanism can be destroyed by treating cancer cells with a drug called decitabine.

The researchers found that when they treated chemotherapy-resistant ovarian and colon cancer cells with decitabine, the cells became sensitive to treatment and could be killed more effectively by a number of chemotherapy drugs.

They are now planning to collaborate with a pharmaceutical company to see whether the drug can do the same in patients' tumours.

If the research, funded by the Cancer Research Campaign, is successful, it could save the lives of many patients whose cancers do not respond to chemotherapy alone.

Frustrating

Lead researcher Professor Bob Brown said: "There is nothing more frustrating than a cancer that appears to be responding to chemotherapy, only to build up resistance against it.

"But drugs such as decitabine should help to overcome that resistance, allowing cancers to be treated more effectively. Our research could provide a way forward for patients that are currently very difficult to treat."

Bizarrely, cancer cells gain their shield against chemotherapy by losing one of their key functions.

Normal cells - and cancer cells that are sensitive to chemotherapy - have a system called mismatch repair which detects errors in DNA and makes sure that genes don't get mutated.

But the same DNA repair system gets fooled by chemotherapy into stimulating cells to commit suicide and may explain how chemotherapy works against certain tumours.

However, if cancer cells lose mismatch repair they become resistant to treatment.

Professor Brown's research has concentrated on finding out exactly how cancer cells come to lose mismatch repair, and how - by restoring the system - they can be made sensitive once more.

His team discovered that in many resistant cancer cells, several key genes, including one called hMlh1, are switched off by a chemical process called DNA methylation.

Switching off gene

It is the switching off of these genes that seems to lead to the loss of mismatch repair.

And by treating cancer cells with decitabine - which is well know for its ability to reverse the process of methylation - the genes can be switched back on, restoring mismatch repair to working order.

Professor Brown said: "This may only be the tip of the iceberg.

"Recent advances in the way we study DNA methylation in the human genome are uncovering many important genes which may be targets for these kinds of drugs."

Dr Mary Berrington, CRC Science Information Manager, said: "Chemotherapy is a powerful weapon against cancer, but too often it loses its effectiveness as tumours develop resistance."

"Professor Brown's research not only sheds light on how this resistance occurs, but may have also shown us an effective way of reversing the process, potentially making many cancers once again sensitive to treatment."

-- Anonymous, July 16, 2001