By quelling a mutant enzyme that can induce bone marrow cells to proliferate wildly, four new drugs stop a deadly form of leukemia in mice. Three of the drugs are now being tested in people who have acute myeloid leukemia, a lethal blood cancer, and plans are under way to start a trial of the fourth.
In this leukemia, bone marrow stem cells multiply out of control and fail to mature into red blood cells or other blood components. The disease `carries a grim prognosis--only 14 percent of patients survive 5 years. Roughly two-fifths of people with the leukemia harbor a mutation in a gene encoding an enzyme called FMS-like tyrosine kinase 3 (FLT3), and this mutation further decreases patients' survival rates.
The FLT3 enzyme plays a role in a cell's growth cycle. In normal marrow cells, the gene encoding FLT3 switches on and off as the cells mature. A mutated FLT3 gene remains active, and the enzyme it produces revs up a chain reaction that leads to aberrant cell proliferation.
"Immature blood cells then crowd out healthy cells and accumulate in the bone marrow," as well as in the liver and spleen, says molecular biologist Louise M. Kelly of the Howard Hughes Medical Institute and Brigham and Women's Hospital in Boston. That causes anemia, organ damage, and other complications.
All four of the new drugs derail the chain reaction by binding to FLT3 and inhibiting its growth-inducing effects.
Only 10 years ago, Kelly says, few people would have believed that inhibiting a single enzyme could stop cancer. That changed when other scientists showed that the drug imatinib mesylate, or Gleevec, can thwart chronic myelogenous leukemia in animals and people by inhibiting another mutant tyrosine kinase (SN: 12/11/99, p. 372; 6/23/01, p. 389).
The success of imatinib mesylate "inspired a lot of people to take an active interest in kinase inactivation," Kelly says.
In two studies in the June Cancer Cell, Kelly and her colleagues report that drugs called PKC412 and CT53518 lock onto FLT3 in lab tests and mouse experiments. Mice injected with cells harboring the FLT3 mutation develop a disease like leukemia. Treatment with either drug seems to get rid of abnormal cells and significantly extends the animals' survival compared with mice not receiving a drug.
PKC412 is manufactured by Novartis Pharma AG of Basel, Switzerland. CT53518, which is now being tested in leukemia patients, is made by Millennium Pharmaceuticals of South San Francisco, Calif.
In the June 1 Blood, Donald Small, a pediatric oncologist at Johns Hopkins University Medical Institutions in Baltimore, and his colleagues report similar results. The drug, called CEP-701, that they used in their experiments on mice is also being tested in leukemia patients. It's made by Cephalon of West Chester, Pa.
A fourth drug, SU11248, is made by Sugen in South San Francisco and is also being tested in patients, says physician James Foran of the University of Nebraska Medical Center in Omaha.
All four drugs are taken orally and produce few side effects. They boost the proportion of healthy cells in the bone marrow of the mice and reduce cell accumulation in the spleen.
The work presented in these studies "is really outstanding," says Arthur E. Frankel, a physician and drug designer at the Wake Forest University School of Medicine in Winston-Salem, N.C. The drugs inhibit a single enzyme, and "they presumably won't work for other leukemias. Luckily, this is one of the most common," he says.
Approximately 10,000 new cases of acute myeloid leukemia are diagnosed each year in the United States. The disease accounts for 90 percent of all adult leukemia cases and claims about 7,200 victims per year in this country and about 30,000 worldwide.
COPYRIGHT 2002 Science Service, Inc.
COPYRIGHT 2002 Gale Group
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