Researchers said on Sunday they had identified a mechanism that enables ovarian cancer -- dubbed a "silent killer" of women for the many lives it reaps -- to evade frontline chemotherapy drugs and rebound.

Ovarian tumours among women who have a cancer-causing variant of a gene called BRCA2 initially respond well to platinum-based drugs such as cisplatin and carboplatin.

But resistance eventually builds in many cases, and doctors have been struggling to explain why.

The explanation lies with newly uncovered mutations in BRCA2, according to two studies, published online by the British journal Nature.

In its healthy form, BRCA2 has the job of repairing damaged DNA.

But a flawed version of BRCA2 disrupts that ability, which increases the risk that mutant cells survive and develop into tumours.

At the same time, though, BRCA2-type cancers are -- initially -- very responsive to chemotherapy.

The newly-discovered mutations act like a switch, which alters the faulty BRCA2 gene in the cancer cell, the scientists believe.

The change restores BRCA2's repair function, enabling the gene to patch up DNA damage done by the platinum drugs and thus allowing the cancer cell to survive.

The mechanism explains why these cancers become resistant to platinum-based drugs, as well as to another class of chemotherapy compounds known as PARP inhibitors.

The findings open the way to better tools to identify which women may be at risk from recurrent ovarian tumours and to new avenues for drugs to block the workings of the flawed BRCA gene, the investigators believe.

"We may be able to better predict who will respond to different chemotherapy agents and find novel ways to re-sensitise tumours to chemotherapy that otherwise would not have had a good response to treatment," said Elizabeth Swisher, a University of Washington professor who co-wrote one of the papers.

The discovery may also help to explain why the resistance problem arises among women with a related gene to BRCA2, called BRCA1.

Culprit versions of both genes may account for about 10 percent of ovarian cancers, the paper suggests.

PARIS, Feb 10, 2008 (AFP)


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