Researchers at the University of Maryland Greenebaum Cancer Center have made a discovery that may explain why some cases of breast cancer and other forms of cancer are resistant to chemotherapy. Their findings, published in the December 22, 1998, issue of Proceedings of the National Academy of Sciences, may lead to better ways to target chemotherapy to individual patients and may open the door to new strategies to reverse resistance to cancer-fighting drugs.
"We have found a cancer resistance protein that rapidly pumps out chemotherapy from a certain line of breast cancer cells," says L. Austin Doyle, M.D., associate professor of medicine at the University of Maryland School of Medicine who is the lead author of the article.
The researchers call the newly-discovered pump Breast Cancer Resistance Protein (BCRP). They found that this protein pumped three common anti-cancer drugs out of cells rapidly, before the drugs could get to the nucleus of the cancer cells and destroy them.
"This is only the fourth molecular drug resistance pump of anti-cancer drugs to be identified, and it is half the size of the other pumps," says Douglas D. Ross, M.D., Ph.D, professor of medicine at the University of Maryland School of Medicine. "We had been looking for years for a way to explain resistance among this group of resistant cancer cells, so this is an important step," adds Dr. Ross, who is a co-author of the article.
The researchers, along with Lynne Abrusso, M.D., Ph.D, assistant professor of pathology at the University of Maryland School of Medicine, studied resistant and non-resistant cancer cells to find genes that were different among the two groups. They used molecular biology techniques to isolate the unique BCRP gene from drug-resistant cancer cells. Then, they tested their theory by changing non-resistant cells into resistant ones by inserting the BCRP gene into them.
"Drug resistance is a big problem for many patients with cancer," says Dr. Doyle. "We are trying to determine which cancers have this type of resistance. In the future, we may be able to help our patients by adding compounds to their chemotherapy that will block the protein products of genes that cause resistance."
One of the drugs these resistant cancer cells are able to pump away is mitoxantrone, a common first-line chemotherapy which is less toxic than many other anti-cancer drugs. It is often prescribed for breast cancer, leukemia, colon cancer and myeloma. "With these findings, we may be able to make this good drug even better," says Dr. Ross.
Mitoxantrone-resistant cell lines from breast, stomach and colon cancers as well as multiple myeloma all were found to have increased levels of the new cancer resistance protein.
The researchers are working on ways to overcome this newly-discovered form of resistance and improve the effectiveness of chemotherapy. Recently, they have tested a new compound that turns off the newly-discovered resistance protein and restores the ability of mitoxantrone and other chemotherapy drugs to kill cancer cells successfully.
Researchers at the University of Maryland Greenebaum Cancer Center are involved in a wide variety of basic and clinical research. The center provides a complete range of specialized services for all aspects of cancer care, and patients have access to promising new therapies before they are widely available.
Reporters note: To receive a copy of the paper, please contact the National Academy of Sciences News Office at 202-334-2138.
Journal
Proceedings of the National Academy of Sciences