New Leukemia Treatment
Given the excitement of a family vacation in California, four-year-old Ashford Slowley's fatigue and loss of appetite did not seem unusual. "The kids were playing hard," says his mother, Tina Slowley. "They don't eat much when they're in the hot sun." But on the long drive north to their home in Richmond, B.C., in April, 1994, Slowley and her husband, Jay, noticed worrisome new symptoms in their son: swollen glands, headaches and small dark bruises on his body. Alarmed, the family stopped at a hospital in Eugene, Ore. - where the boy was diagnosed with acute lymphoblastic leukemia, the most common childhood cancer. Rushed by jet to British Columbia's Children's Hospital in Vancouver, Ashford was placed on radiation and chemotherapy. "If everything goes smoothly," says Tina, "he should stop his chemo in July." And the prognosis is hopeful: the treatment doctors are administering to Ashford eliminates the disease in more than 70 per cent of cases. Now, researchers in Toronto and Israel say that they may be able to improve the odds for children with leukemia - with a new drug that has the potential to cure the critically ill youngsters who do not respond to chemotherapy.
The breakthrough, reported last week in the British journal Nature by researchers at the Hospital for Sick Children in Toronto and Hebrew University in Jerusalem, takes the decades-old fight against cancer in a new direction. "This is a completely novel approach that makes sense," said Dr. Max Coppes, director of oncology at the Alberta Children's Hospital in Calgary, after reviewing the report. "On a scale of one to 10, I would rate it as an eight or nine in potential impact." Coppes compares traditional chemotherapy to an atomic bomb - "You throw it in and kill the cancer cells and everything that's around them," he says. "Then you hope that after the blast, there are enough healthy cells so that the kid can continue living." But the new drug, called AG-490, after the initials of Aviv Gazit, a scientist on the Israeli research team, appears to work selectively. Like a smart bomb, it targets and kills cancer cells without affecting healthy tissue. "The concept is exciting," says immunologist Dr. Chaim Roifman, head of the research team at Toronto's Hospital for Sick Children, "because it can - and should - be applied to many other different kinds of cancer."
The discovery came after Roifman turned his attention to the study of the basic mechanism of cells. Last year, he pinpointed a group of about 70 enzymes called kinases, which transmit signals for the growth of a cell. "We identified the enzymes in normal cells and in leukemia cells," he explains. "We found that one of them is abundant in leukemia cells." The Toronto researchers - as yet unaware of the enzyme's importance - named it Jak-2, for "just another kinase." At the same time, the collaborating Israeli team, led by biochemist Alexander Levitzki, began synthesizing compounds in an attempt to find a chemical that could block the enzyme and stop the proliferation of cancer cells. The researchers were lucky. Although there were thousands of possibilities, they found the right fit after a mere 60 attempts. "It was a perfect match," says Roifman. "Our drug binds directly to the enzyme related to cell division, arrests the growth process - and the cancer cell dies."
The Toronto researchers achieved impressive results when they tested the drug on human leukemia cells implanted in mice. "At therapeutic levels, there is 100-per-cent elimination of leukemia," says Roifman, adding that "the affected mice seem to be very happy." Roifman - whose research is funded by the National Cancer Institute of Canada, the Medical Research Council of Canada and sugen Inc., a California-based pharmaceutical company - also believes that the drug will have few, if any, side-effects. "Normal tissue and normal bone marrow appear not to be affected at all," he says.
The drug could potentially cure the approximately 220 children afflicted by childhood leukemia each year. But Roifman says that his team's plan of attack - to pinpoint and block the parts of cells responsible for the proliferation of leukemia - holds promise for the treatment of other forms of the disease. Among the likely targets of the approach are breast cancer and prostate cancer, which have levels of enzymes similar to those in childhood leukemia.
Roifman cautions that it could take at least three to seven years before the drug is ready for clinical use. "We do not have a drug suitable for human use tomorrow morning," he says. Oncologist Coppes also tempers his enthusiasm. "I don't see any treatment changes round the corner," he warns. "There are some issues that still need to be resolved." The investigators still need to prove that blocking the action of one enzyme will result in longtime survival for the patient, says Coppes. "A cure is determined by the fact that a child is alive after five years," he argues. Roifman agrees that there is much work to be done on AG-490 - but says that the need for its development is pressing. At the Hospital for Sick Children, "we see the worst cases of leukemia," he adds. "There is a lot of suffering - it would be fantastic to be able to help them."
Maclean's February 26, 1996