11 Feb 2008 (Sawf News) - A team of researchers led by Fred Hutchinson Cancer Research Center has identified a new mechanism that explains why some recurrent ovarian tumors become resistant to treatment with commonly used platinum-based chemotherapy drugs such as cisplatin and carboplatin.

While ovarian tumors initially respond very well to platinum-based chemotherapy drugs such as cisplatin and carboplatin, eventually between 70 percent and 80 percent of advanced-stage ovarian-cancer patients develop a resistance to these drugs. BRCA2 works to repair damaged DNA; inherited mutations in this gene disrupt that ability, which increases the risk of ovarian and breast cancer. At the same time, such mutations also make cancer cells more vulnerable to DNA-damaging agents found in cisplatin and carboplatin.

The new discovery found that when exposed to cisplatin, some ovarian-cancer cells develop secondary mutations on their BRCA2 gene that restore the gene’s ability to repair DNA. This restoration of gene function then makes the cancer cells resistant to chemotherapy.

If women with recurrent ovarian cancer are found to have a secondary mutation on their BRCA2 gene, their cancer likely would be resistant not only to platinum-based compounds but also other drugs such as PARP inhibitors.

Testing whether relapsed tumors have a secondary mutation of BRCA2 may be important to predict clinical outcome.

The researchers suspect they may be able to generalize their findings regarding secondary mutations in BRCA2 to other DNA-repair genes, such as BRCA1, which may help explain drug resistance to a variety of cancers, including those of the breast, prostate and pancreas.

These findings may also help to explain the mechanics of cisplatin resistance in ovarian-cancer patients with BRCA1-gene mutations Together such genetic mistakes are thought to cause about 10 percent of ovarian cancers

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