New Drug Tackles Gleevec Resistance in Mice — May Help Leukemia Patience

An article published in the July 16 issue of Science reports on efforts to find a compound that can reduce or eliminate resistance to a treatment for chronic myeloid leukemia (CML).

According to the National Institutes of Health, CML is “a cancer of blood cells, characterized by replacement of the bone marrow with malignant, leukemic cells.” CML is a genetic disease in which chromosome translocation causes an enzyme to signal for the body to produce excessive levels of white blood cells.

CML, however, is one of the few cancers that has an effective treatment. A drug called Gleevec was created specifically to interfere with the enzyme, thus stopping the overproduction of white blood cells.

There’s just one problem — there are a number of known genetic mutations which cause Gleevec to fail to work. For individuals with those particular mutations, Gleevec will not work.

Which is where a group of researchers from Howard Hughes Medical Institute, UCLA’s Jonsson Comprehensive Cancer Center and Bristol-Myers Squibb enter with research on a compound called BMS-354825. BMS-354825 is a compound designed to have the same effect as Gleevec while sidestepping that compound’s vulnerability to a number of genetic mutations.

In the Science article, HHMI investigator Charles Sawyers reports that the results of mice studies demonstrate that BMS-354825 virtually stopped CML in mice who have genetic mutations similar to those that cause Gleevec resistance in human beings. The researchers also demonstrated that BMS-354825 inhibits the production of diseased bone marrow progenitor cells in cultured human bone marrow cells taken from patients who are resistant to Gleevec.

Clinical research of BMS-354825 is still years away, and any number of problems could prevent the drug from being as effective in human beings as it is in mice. Still it is important to note that Gleevec, which has extended the lives of so many of those afflicted with CML, was the product of animal research as well.

In 1990, researchers at a number of laboratories demonstrated with a mice model of the disease that it was caused by a defective protein, BCR-ABL. In 1996, researchers demonstrated that Gleevec inhibited the growth of cells that expressed BCR-ABL in mice and later that it eradicated CML tumors in nude mice. In addition, pre-clinical toxicology testing in animals indicated the drug was safe enough to proceed with clinical trials.


New drug shows promise against Gleevec resistance in mice. Press Release, Howard Hughes Medical Institute, July 15, 2004.

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