February 14, 1996
Novel treatment concept blocks signals that control growth of leukemia cells
TORONTO - Researchers at Toronto's Hospital for Sick Children (SickKids) have developed a novel concept for anti-cancer treatment of recurrent acute lymphoblastic leukemia, the most common form of childhood cancer. Their approach is to selectively block an intracellular transmitter of signals which control the growth of leukemia cells.
The research was conducted at SickKids under the leadership of Dr. Chaim Roifman, head of the Immunology & Allergy division at SickKids and associate professor of Pediatrics, University of Toronto. The work is described in the February 15 issue of Nature.
"This advance is particularly exciting because there's a real possibility that our approach can be applied not only to leukemia, but to other types of cancers as well," Dr. Roifman explains.
Researchers have demonstrated - for the first time - that the enzyme Jak-2, which acts as a transmitter of cell growth signals, is overabundant and abnormally active in recurrent leukemia cells. This causes the leukemia cells to reproduce uncontrollably.
Dr. Roifman and colleagues screened a variety of compounds which have the potential to block the activity of Jak-2. They discovered that the compound AG-490 inhibited the function of Jak-2 but not other enzymes and killed leukemia cells in vitro. (The compounds were prepared by collaborators Drs. Alexander Levitzki and Aviv Gazit of the Hebrew University, Jerusalem.)
"We also found that AG-490 was effective in eliminating leukemia growth in immunodeficient mice which had been transplanted with human leukemia cells," Dr. Roifman explains. "The AG-490 had no adverse effect on their normal blood system, indicating that this compound is also very effective in vivo."
In acute lymphoblastic leukemia, an excessive number of abnormal immature white blood cells (called blasts) are produced in the bone marrow. These immature cells are driven by growth factors and their receptors which are expressed in leukemia. Central to transmission of cell growth signals through such receptors are a family of enzymes, including Jak-2.
The acute form of the disease progresses very rapidly. Despite progress in treatment, 20 percent of patients will relapse and no longer respond to chemotherapy.
"While this work is extremely promising, we are at least three to five years away from developing an effective drug suitable for human use," cautions Dr. Roifman.
This research was supported by the National Cancer Institute of Canada, the Medical Research Council of Canada, and SUGEN, Inc.
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