A new class of drugs proven in high doses to have effective anti-tumor effects reduces the severity of graft-versus-host disease in mice after marrow transplantation without suppressing immune-system ability to kill cancer cells, according to an article published online March 4th by the Proceedings of the National Academy of Sciences.

The drugs, called histone deacetylase inhibitors (or HDAC inhibitors), have already been tested in clinical trials and found to be effective anti-tumor agents. In the current work, researchers found that doses 50- to 100-fold lower than that necessary for cytotoxicity produce a powerful anti-inflammatory effect, preventing production of the inflammatory cytokines that cause the extensive cell damage characteristic of graft-versus-host disease.

Currently, more than 5,000 Americans receive allogeneic bone marrow transplants annually. Roughly 500 to 1,000 people die from graft-versus-host disease each year. The American research team conducted two sets of experiments with strains of laboratory mice commonly used in research related to bone marrow transplants. In the first experiment, three groups of mice were given standard bone marrow transplants. Mice received bone marrow from either allogeneic or syngeneic donors.

Between day 3 and day 7 after the transplant, scientists gave low doses of an HDAC inhibitor called suberoylanilide hydroxamic acid to one group of experimental mice that received allogeneic transplants. When researchers compared results in these mice to results in mice given the same type of bone marrow transplant but not the HDAC inhibitor, they found a number of differences:

Use of the HDAC inhibitor was associated with a survival rate that was 60 percent higher than that seen in matched mice not given the drug. In addition, although some of the HDAC-treated mice developed graft-versus-host disease, they had milder symptoms and less intestinal damage than mice that did not receive the drug. Finally, the drug had no apparent effect on how donor T cells responded to host antigens by binding to cancer cells and killing them.

To find out whether the drug or immune system activity was responsible for tumor-free survival of mice in the study, the group conducted a second series of experiments. This time, they gave experimental mice a lethal dose of leukemia cells in addition to either an allogeneic or syngeneic bone marrow transplant.

All mice given a syngeneic transplant and drug treatment died from their cancer, whereas 50 percent of mice given an allogeneic transplant and the drug survived. “In syngeneic transplants, the donor cells are genetically identical to the host, so they won’t react to foreign antigens on host cancer cells,” Pavan Reddy, MD, lead author of the study, explained. “The fact that all the syngeneic transplant mice died of cancer suggests that donor T cells and graft-versus-leukemia effect ? not the drug ? were killing the malignant cells.”

Scientists know all too well that what works in mice doesn’t always work in people, but Reddy is cautiously optimistic. “When HDAC inhibitors were tested in mice and in clinical trials with leukemia patients, researchers found the same anti-tumor effect,” he said. “The mice we selected for this research are known to be good models for what happens in humans after a bone marrow transplant. So there are reasons to believe that we may see the same anti-inflammatory effects in people, as well. But this will need to be determined in well-designed clinical studies.”