Leukemic cells rehabilitated in rats.

Leukemic cells rehabilitated in rats

The odds that an individual will survive a bout with leukemia depend not only on the strength of that person's immune response, but also on his or her supply of a little-understood class of biological substances called differentiation factors, new research suggests. It is believed that one anticancer drug now in clinical trials--called granulocyte colony stimulating factor--may be a member of this mysterious class of substances, but nobody is really sure how many of these factors exist or how they work. Indeed, until now, all that's been known is that there is something in the extracts of certain mammalian organs that has the ability to induce differentiation (normal maturation) in cultured leukemic cells.

The new work is the first to quantify the effects of these factors on leukemia cells in living rats, and suggests that they may be more important as cancer-protective factors than researchers in the field previously believed.

The research, which appears in the Nov. 27 SCIENCE, was performed by Joaquin J. Jimenez and Adel A. Yunis of the University of Miami School of Medicine. They worked with myeloid leukemia cells, which are white blood cells that have failed to differentiate into their mature forms and that continue to proliferate indefinitely.

"Lots of people have shown that you can induce differentiation of cells in vitro' with the addition of a differentiation factor, Yunis says. "Our research attempts to answer one question: If you can push a leukemic cell to differentiate in the test tube, what then keeps it in a constantly self-renewing, undifferentiated state' in animals or patients with leukemia? The answer, he says, may be that leukemic patients are unable to generate by themselves appropriate amounts of that differentiation factor.

To test this hypothesis, Jimenez and Yunis extracted quantities of the factor from a variety of rat organs and performed experiments on test tube cultures of leukemic cells. They found that the more differentiation factor they added to the cells, the greater the number of leukemic cells could be induced to differentiate into normal, adult white cells. In similar experiments using live animals, the researchers found that rats given higher doses of differentiation factor were better able to survive injections of leukemic cells.

But because scientists still do not know the molecular structure of differentiation factor and can only deduce its presence in extracts by its action on cells, it was important to show that the rats' increased survival was due to an induced, normal differentiation of their leukemic cells and not to an immune factor that simply killed the leukemic cells. To find out, the researchers implanted into rats tiny screened cages, or diffusion chambers, containing a known number of leukemia cells. Cells could not enter or leave the chambers, but were bathed in the rats' body fluids--including various concentrations of injected differentiation factor.

After 48 hours, they retrieved the chambers and examined the cells. In rats with higher levels of circulating differentiation factor, 90 percent of the cells were still alive and 94 percent of them had differentiated. The rampant replication characteristic of leukemic cells had stopped. In control rats with no differentiation factor added, none of the trapped cells differentiated and cell proliferation continued unchecked.

The next steps are to purify, identify and try to mass-produce the factor or factors responsible for this differentiating activity, Yunis says. "As we get closer to purifying these factors, we should be able to get answers about how they work,' he says.

"But whatever the mechanism is, and whatever these factors are, the experiment tells us that you can push these leukemic cells to differentiate in vivo. It indicates that the use of [supplemental] differentiation factor has potential therapeutic application.'