Researchers at the University of California, San Diego (UCSD) Cancer Center have discovered a way to trick leukemia cells into committing suicide by using the gene that causes the leukemia in the first place.
Using a two-drug combination, the researchers were able to coax a deadly cancer-causing molecule called Bcr-Abl from its command center in the cell cytoplasm, push it deep into the cell nucleus, and trap it there. With no escape the oncogene gives a self-destruct order and the cancer cell commits suicide, dissolving into harmless cellular dust.
The research team - Jean Y.J. Wang, Ph.D., Associate Director for Basic Research at UCSD Cancer Center and UCSD Herbert Stern Professor of Biology, and research fellow Paolo Vigneri, M.D., Ph.D. - report their findings in the February 2001 issue of the journal Nature Medicine.
Bcr-Abl is an abnormal protein that forms when the chromosomes housing the Bcr gene (chromosome 22) and the Abl gene (chromosome 9) are broken after exposure to radiation or other factors, and then mistakenly joined together by the body's normal DNA-repair function. This single oncogene causes chronic myelogenous leukemia (CML), a lethal disease that constitutes 15 to 20 percent of all adult leukemias and affects approximately 50,000 people a year worldwide.
Researchers at the pharmaceutical company Novartis have isolated a drug, STI571, that can inhibit the function of Bcr-Abl. STI571 has shown enormous promise in clinical trials on CML patients at the early phase of this disease; however, STI571 alone is not as effective in treating patients who have progressed to a more advanced stage of CML.
In their experiments with STI571 in leukemia cells, Vigneri and Wang discovered that Bcr-Abl is not only inhibited, but also mobilized by this drug.
Bcr-Abl stimulates the abnormal proliferation of blood cells and does so from the cytoplasm of the leukemia cells. Bcr-Abl has never been detected in the nucleus, where the genomic DNA resides. Vigneri and Wang discovered that STI571 can mobilize Bcr-Abl to enter the nucleus, but the leukemia cells quickly spit it back out to the cytoplasm. They therefore applied a second drug, Leptomycin B, to seal the port for nuclear export and thus succeeded in trapping Bcr-Abl in the nucleus.
Taking clues from other studies conducted in Wang's laboratory, they thought nuclear Bcr-Abl might activate the cellular suicide program. They have now shown that this prediction is indeed correct - the combined treatment with STI571 and Leptomycin B causes CML cells to commit suicide. They have achieved a complete eradication of CML cells in culture dishes after a three-day treatment with these two drugs, when either drug alone was unable to kill off these advanced leukemia cells.
The UCSD Cancer Center has assembled a team of researchers to test this combination of two drugs in a pre-clinical study.
"This work not only holds promise for a potential cure of CML, it also opens a whole new area of research that may lead to similar approaches to treat other types of cancer," said David Tarin, M.D., Ph.D., director of UCSD Cancer Center. "It is a good example of the Cancer Center's endeavors to translate basic science discoveries into clinical benefit for patients."
This work was supported by grants from the National Institutes of Health and a fellowship from the Pete Lopiccola Memorial Foundation.
Founded in 1979, the UCSD Cancer Center is one of just 60 centers in the United States to hold a National Cancer Institute (NCI) designation. As such, it ranks among the top centers in the nation conducting basic and clinical cancer research, and providing advanced patient care. The Center's mission is to translate promising scientific discoveries into new and better options for the prevention, diagnosis and treatment of cancer, and the amelioration of pain.
For further information on CML, please visit: http://cancernet.
For a copy of the manuscript, please contact Nancy Stringer (contact info above).