Researchers at The University of Texas M. D. Anderson Cancer Center have found, in laboratory studies, that the experimental drug ABT-737 which has shown promise in some cancers, can destroy acute myeloid leukemia (AML) blast, progenitor and even stem cells that are often resistant to standard chemotherapy treatment.
The drug was powerful in its own right, the researchers say, but they found that some AML cells were themselves resistant to ABT-737, so they added another drug that knocked out this secondary resistance. Together, these agents may provide a powerful therapy against AML, and could form the basis of a new way to treat the cancer, say the scientists, whose study was published in the November 14 issue of the journal, Cancer Cell.
"The combination of these two experimental drugs provides the highest synergistic action I have ever seen against acute myeloid leukemia cells," said the study's lead author, Michael Andreeff, M.D., Ph.D., professor in the Departments of Stem Cell Transplantation and Leukemia.
Although the study was done in laboratory cell cultures and AML cells obtained from patients, Andreeff said he hopes that a combination of these two agents could be tested in eligible patients when they receive standard chemotherapy treatment. "ABT-737 would overcome resistance to chemotherapy that we often see in AML therapy, and the second drug would overcome resistance to ABT-737," he said.
"ABT-737 represents a completely new class of agents that could have a major impact on a number of cancers, and we have now seen that AML will likely be among them," Andreeff added.
The successful use of ABT-737 in animal models of human small-cell lung cancer and cancers of the lymph system were reported in 2005 by researchers from Abbott Laboratories, which developed the compound.
The agent works by manipulating members of the BCL-2 family of proteins, which includes both pro-apoptotic and anti-apoptotic molecules. (Apoptosis is a process whereby a cell kills itself because it is seriously injured or growing out of control).
ABT-737 targets the best-known member of the group, also called BCL-2, which is a cell "survival" protein that is over-expressed in many types of cancer. This protein prevents a cell from committing apoptosis by latching on to other BCL-2 family member proteins that promote cell death, thus rendering them ineffective. ABT-737, however, was engineered to fit tightly on to BCL-2, occupying that binding space so that the other pro-apoptotic proteins can function and promote cell death.
In this study, Andreeff and a team of researchers found that ABT-737 "potently" kills AML cell lines as well as blast cells taken from AML patients. "Most importantly, our results demonstrated killing of the progenitor and stem cells responsible for production of AML, which makes this a truly innovative treatment for different leukemias and cancer," Andreeff said.