Aug. 14, 1998 LOS ANGELES (July 21, 1998) -- Breast cancer cells exposed to a diabetes drug and the Vitamin A compound Accutane stopped multiplying and died on cue in laboratory and animal studies conducted at Cedars-Sinai Medical Center, researchers reported today in the journal Proceedings of the National Academy of Science.
Troglitazone, an antidiabetes drug, and Accutane, a Vitamin A compound used to treat severe acne, appear to work synergistically in permanently inhibiting cell growth and inducing apoptosis (programmed cell death) in breast cancer cells.
"Troglitazone alone has a mild effect on breast cancer cells. Accutane alone has a mild effect on breast cancer cells. Together, they have a dramatic effect," said Dr. H. Phillip Koeffler, Director of Hematology/Oncology at Cedars-Sinai Medical Center and Professor of Medicine at the University of California, Los Angeles.
Breast cancer cells stay young and vigorous, proliferating wildly while normal cells around them perform their functions, then mature and die as other cells replace them, Dr. Koeffler explained. The highly selective approach he and his team used not only deprives breast cancer cells of the protein energy source that makes them grow, but also programs them to age and die on schedule.
Importantly, the drug combination appears to have no adverse effect on healthy cells, either in laboratory studies or in immunodeficient mice injected with human breast cells that form tumors.
The way in which the drugs work is not fully understood, although their success is probably due to their targeting of distinct receptors on breast cancer cells that give them an edge over other cells, Dr. Koeffler said.
Troglitazone binds two receptors found in tumor cells: a steroid receptor called peroxisome proliferator-activated receptor gamma (PPARg), and a retinoid (Vitamin A) receptor. Accutane may then bind to this combined receptor. The activated receptor complex causes a protected gene within the cancer cell to be modulated.
That gene, bcl-2, is associated with programmed cell death. At high levels, it prevents cell death. At low levels, it induces cell death. "When exposed to the two-drug combination, cancer cells express almost undetectable levels of bcl-2," Dr. Koeffler said.
Since results of the in vitro (laboratory) and animal experiments were successful, preliminary research has begun to determine whether the drug combination is successful in humans. The first patient with prostate cancer has been enrolled in a study of troglitazone, and a small trial involving women with metastatic breast cancer will soon be underway.
New cancer drugs are often first tested on patients with advanced disease, explained Dr. Koeffler, since proved therapies exist for those with more treatable, early-stage cancer. If the results are promising in the most-difficult-to-treat patients, research begins on patients with less advanced disease, he said.
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