The work highlights the new field of pharmacogenomic therapy, which has become increasingly important with the sequencing of the human genome and, it is hoped, will lead to improved cancer therapies.

The findings, reported Tuesday at the annual meeting of the American Association for Cancer Research in New Orleans, may warrant oncologists to reconsider using certain chemotherapy agents for those women with breast cancer who carry the altered gene, known as BRCA1.

The scientists, led by Bruce Turner, M.D., Ph.D., assistant professor of radiation oncology at Jefferson Medical College of Thomas Jefferson University in Philadelphia and at Jefferson's Kimmel Cancer Center and John C. Reed, M.D., Ph.D., Scientific Director of the Burnham Institute in La Jolla, found that breast cancer cells with mutations in BRCA1 are sensitive to certain chemotherapy drugs and radiation, but resistant to others, such as the widely used anti-breast cancer drugs taxol and taxotere.

These drugs are frequently used in combinations with other chemotherapy agents in young women with breast cancer or in those with advanced disease.

When the researchers looked at breast tumors in women with BRCA1 mutations, they found cancer cells lacking the Bcl-2 gene protein, which appears important for the effectiveness of taxol and which also inhibits apoptosis, or programmed cell death.

Dr. Turner and his co-workers found that normal BRCA1 regulates Bcl-2 gene expression on a molecular level and this regulation may be important in prodding breast cancer cells into cell death in response to DNA-damaging agents such as cisplatin, adriamycin, taxol and radiation.

However, patients with hereditary breast cancer with mutations in the BRCA1 gene have low levels of Bcl-2 protein. "This may be critical in the observed lack of response to taxol in breast cancer cells with BRCA1 mutations," Dr. Turner says.

"The finding has important clinical applications," Dr. Turner added. "This suggests that women with BRCA1 mutations would not be good candidates for certain types of chemotherapy agents like taxol and may suggest that they are better candidates for drugs such as adriamycin, cisplatin and other newly discovered agents."

The latter drugs work differently than taxol: They interact directly with DNA, and their activity is independent from the Bcl-2 protein.

"It also explains the lack of response in cells that have been treated with taxanes," Dr. Turner says. "We found that if there is a mutation in BRCA1, breast cancer cells are not able to induce expression of Bcl-2 protein, which also functions to inhibit cell death.

"Cells lacking Bcl-2 should be sensitive to DNA-interacting drugs and the lack of Bcl-2 should result in resistance to taxol, which is exactly what we found. It appears this is all the result of a mutation in BRCA1, since BRCA1 appears to be an important regulator of Bcl-2 gene expression."

Dr. Turner and his co-workers believe that this work is an important example of the potential of pharmacogenomic therapy in identifying small groups of patients with specific genetic changes that respond to specific drugs. One day, they say, this type of gene-drug interaction may result in improved patient responses to drugs and survival.

28-Mar-2001