DALLAS – May 2, 2005 – A new experimental drug may be effective against a certain form of leukemia resistant to current treatments, research at UT Southwestern Medical Center shows.
"This novel anti-leukemia drug that we have been working on shows considerable promise for going into the clinic," said Dr. Robert Ilaria Jr., associate professor of internal medicine and molecular biology and senior author of the study that will appear in an upcoming issue of Blood. The study is available online.
The study on the drug, called PD166326, was done in mice with a form of leukemia similar to human chronic myelogenous leukemia (CML), which is diagnosed in about 5,000 people in the United States each year. Patients with CML produce a mutated enzyme that stimulates white blood cells to overproduce, causing leukemia.
The Blood study shows that PD166326 is nearly 100 times more potent than the current drug imatinib (Gleevec) against cells expressing this enzyme, Dr. Ilaria said.
"Our study represents the first published characterization of this novel anti-leukemia drug in animals," Dr. Ilaria said. Gleevec is approved by the Food and Drug Administration for the treatment of patients with CML. The drug blocks signals within cancer cells and prevents a series of chemical reactions that cause the cells to grow and divide.
Although Gleevec has been highly successful against CML, it is unknown whether the drug can permanently eradicate all leukemia cells with the specific aberrant enzyme found in CML patients. About 15 percent to 20 percent of patients who take Gleevec become resistant to the drug and relapse, leaving few effective treatment options.
In the Blood study, Dr. Ilaria and his colleagues introduced the cancer-causing enzyme into mouse bone-marrow cells to generate mice with a form of leukemia similar to human CML. The disease usually develops slowly, although it can progress to an accelerated phase.
When mice received a single oral dose of PD166326, the mutated enzyme activity was rapidly inhibited, and the white blood count significantly decreased. Two-thirds of the PD166326-treated mice also had complete recovery from splenomegaly, an abnormal enlargement of the spleen, compared to none treated with Gleevec, Dr. Ilaria said.
In long-term use, PD166326 showed better anti-leukemia activity than Gleevec, and it also prolonged the survival of mice with the CML-like leukemia resistant to Gleevec treatment.
While PD166326 is not yet available for clinical trials, investigators at Memorial Sloan-Kettering Cancer Center in New York, who synthesized the drug, are working with a major pharmaceutical company that owns the patent for this class of drugs on its clinical development, Dr. Ilaria said. Its relatively long half-life in mice indicates once-daily dosing might be possible in humans.
PD166326 is in a different class of anti-leukemia drugs currently being investigated by other researchers for their effectiveness in Gleevec-resistant patients. Dr. Ilaria's lab is continuing research in Gleevec resistance and looking at combining this new compound with other drugs.
"CML patients may soon have multiple choices with Gleevec and any one or all of the additional classes of drugs in development," Dr. Ilaria said. "These compounds also may work on other solid tumors, so it will be very interesting to see how it all pans out."
Nicholas C. Wolff, research associate in the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research, is first author of the Blood study.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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