Tumor cell sensitivity - then resistance - to chemotherapy linked to gene.

2003 JUN 5 - (NewsRx.com & NewsRx.net) -- Researchers at Dana-Farber Cancer Institute and a team of international collaborators have identified a genetic abnormality that makes some ovarian tumor cells initially sensitive to a common chemotherapy agent, cisplatin, and then resistant to the drug over time.

Published in Nature Medicine, the study challenges conventional thinking about how cancer cells are able to "outsmart" therapies that at first are effective against them.

"It has been thought that as normal cells evolve into cancerous ones, they acquire more and more genetic damage - to the point where they gain the ability to withstand drugs that once killed them," said the study's senior author, Alan D'Andrea, MD, of Dana-Farber and Children's Hospital Boston. "While that may indeed take place, our study points to another possibility: that cancer cells can, in effect, 'go backward,' switching some genes to a normal state so they essentially disguise themselves from common therapeutic agents."

The finding represents both a hurdle to the development of new anti-cancer drugs and, paradoxically, a crucial step toward the discovery of such drugs. Scientists working on drug development now know that they are chasing more of a moving target than they may have realized. They also have a better sense, however, of how to counter these cellular shifts.

The new study stems from D'Andrea's research in Fanconi anemia, an inherited condition that places children at risk for bone marrow failure early in life and various forms of cancer as they get older. The disease is caused by a defect in any of seven genes that act as a tag-team to repair damaged DNA. Over the last few years, D'Andrea and his colleagues found that this gene "pathway" leads directly to BRCA1 and BRCA2, two of the best known cancer genes in human cells. When either of the BRCA genes or any of those in the Fanconi pathway are mutated, the result can be breast cancer, ovarian cancer, or any of a variety of other malignancies.

When the Fanconi-BRCA pathway doesn't function properly, the DNA in ovarian cells tends to snap and recombine in abnormal ways. This causes the cells to become cancerous, but it also makes them highly susceptible to cisplatin.

"Cisplatin has been a front-line chemotherapy drug for ovarian and other cancers for decades," explained the study's first author, Toshiyasu Taniguchi, MD, PhD, a pediatric oncologist at Dana-Farber and Children's Hospital. "It's one of the more selective agents in our arsenal: it kills cancer cells effectively but doesn't do a great deal of harm to normal tissue."