Magazine article Science News

Leukemia Overpowers Drug in Two Ways

Magazine article Science News

Leukemia Overpowers Drug in Two Ways

Article excerpt

The medicine known commercially as Gleevec serves as a powerful weapon for people fighting the blood cancer called chronic myelogenous leukemia, or CML. Although the drug appears to cure many patients, it usually provides only fleeting improvement for those who have entered the crisis stage of the lethal disease.

A new finding could help scientists patch this weakness in the drug's otherwise potent assault on CML. In an upcoming issue of SCIENCE, researchers at the University of California, Los Angeles (UCLA) reveal how this cancer rebounds.

The leukemia originates when pieces of chromosomes 9 and 22 fuse, forming a hybrid gene called Bcr-Abl (SN: 12/11/99, p. 372). This mutation encodes an enzyme, Bcr-Abl tyrosine kinase, that causes white blood cells to proliferate. Without Gleevec treatment, CML would smolder for years. Eventually, it would explode into a crisis stage in which white blood cells multiply rapidly and crowd out healthy cells in the bone marrow.

The oral drug, also known as STI-571, works by binding to Bcr-Abl tyrosine kinase on CML cells, thereby disabling them. The researchers find that in patients in the crisis stage who relapse despite treatment, this action is subverted or the drug is simply overwhelmed.

Recent studies have revealed some of the biochemistry underlying the leukemia. In CML cells, Bcr-Abl tyrosine kinase adds phosphate groups to a protein called Crkl. This phosphorylated protein, in turn, binds to the kinase and links it to other proteins in a chain reaction that triggers white blood cell proliferation. Bcr-Abl tyrosine kinase is difficult to track in the blood, however, so the team monitored Crkl to gauge the enzyme's activity.

In four untreated CML patients, the UCLA group found that the rate of Crkl phosphorylation in cancerous bone marrow cells was roughly three times that of the disabled cancer cells in eight patients treated effectively with STI-571. …

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