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The Pyrenean ibex, an impressive mountain goat that lived in the central Pyrenees in Spain, went extinct in 2000. But a...
Tight budgets are forcing NASA to consider turning off one or more planetary science projects that have completed their...
Ebola is not a stranger to West Africa—an outbreak in the 1990s killed chimpanzees and sickened one researcher. But the...
In an as-yet-unpublished report, an international panel of geoscientists has concluded that a pair of deadly...
Tropical disease experts tried and failed before to eradicate yaws, a rare disfiguring disease of poor countries. Now,...
Since 2002, researchers have reported that agricultural communities in the hot and humid Pacific Coast of Central...
Balkan endemic kidney disease surfaced in the 1950s and for decades defied attempts to finger the cause. It occurred...
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Why Some Leukemias Resist New Drug
21 June 2001 7:00 pm
The antileukemia drug known as Gleevec or STI-571 has been heralded as the vanguard of a new generation of designer cancer drugs. Unfortunately, some advanced leukemias become resistant to the treatment. Now a new study shows that this resistance can be caused by either mutation or amplification of the gene that makes the drug's target.
Most cancer drugs were discovered by randomly screening thousands of chemicals to see if any kill cancer cells. But STI-571 was designed specifically to inhibit certain kinase enzymes, including the one produced by the Bcr-Abl oncogene, which fuels cancer cell growth in chronic myeloid leukemia (CML). Almost all patients treated in the early stages of CML respond to the drug, and some have been in remission for more than 2 years. But the drug has been less effective in patients who are in an advanced phase of the disease. These individuals sometimes go into remission on the drug--which almost never happens with older treatments--but 80% relapse in less than a year.
To pin down the mechanism for that resistance, Charles Sawyers of the University of California, Los Angeles, and his colleagues first assayed the level of Bcr-Abl kinase activity in tumor cells from 11 patients who had relapsed. They detected high levels in all the cells--an unexpected finding, because such cells are genetically unstable and might have counteracted the drug via some other change. In six patients, the cause turned out to be a point mutation that altered the Bcr-Abl enzyme, allowing it to evade the drug while still retaining the kinase activity that drives tumor cell growth. In three others, extra copies of the gene overwhelmed the drug by producing more enzyme than it could handle.
The fact that changes in the target enzyme are responsible for drug resistance is encouraging, says Brian Druker of Oregon Health Sciences University in Portland, because it means that targeting the Bcr-Abl kinase or the proteins it interacts with is still a promising strategy for combating the cancer. Possibilities for future treatments include designing additional kinase inhibitors that would be given along with STI-571, because the enzyme should be less able to become resistant to all the drugs at once.