Featured Research

from universities, journals, and other organizations

Experimental Drug Shows Promise In Targeting Leukemic Stem Cells

Date:
December 28, 2006
Source:
University of Texas M. D. Anderson Cancer Center
Summary:
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.

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.

However, AML cells in which another anti-apoptotic protein known as MCL-1 is over expressed did not die, which makes this protein a "resistance factor" to ABT-737 and to standard chemotherapy, he said. "In myeloid leukemia, MCL-1 can be more important than BCL-2 because when a cell has a significant amount of MCL-1, many drugs don't work," said Andreeff. In fact, he added, patients whose cells over-express MCL-1 were found by his group to have a poorer outcome.

So, the researchers added an experimental drug, a MAP-kinase inhibitor, to knock down MCL-1 expression, and found that this inhibitor also worked to inhibit cells in which BCL-2 is phosphorylated, which can switch a protein on or off. "ABT-737 had diminished effects against cells with phosphorylated BCL-2, which was restored by combination with a MAPK inhibitor," Andreeff said.

The study helps refine the understanding of the effects of ABT-737 on cancer cells, he said.

By using knock-out technology, the researchers also found that in leukemia cells, ABT-737 was dependent on two proteins called BAX and BAK to trigger apoptosis. Other researchers have said that the critical partner to ABT-737 was a similar protein known as BIM. "Both of these proteins poke holes in a cell mitochondria and release proteins that initiate cell death, but it is important to know that BAX and BAK are the important players," he said.

Andreeff said that the next step for M. D. Anderson researchers is to test ABT-737 in patients with leukemias.

The study was funded by the National Cancer Institute, through a large Program Project Grant, headed by Andreeff.

The first author was Dr. Marina Konopleva, M.D., Ph.D., assistant professor in the Department of Stem Cell Transplantation. Working with M. D. Anderson researchers were scientists from The University of Texas Health Science Center at Houston, the University of Florida Shands Cancer Center, East Carolina University, the University of Michigan and Burnham Institute for Medical Research.


Story Source:

The above story is based on materials provided by University of Texas M. D. Anderson Cancer Center. Note: Materials may be edited for content and length.


Cite This Page:

University of Texas M. D. Anderson Cancer Center. "Experimental Drug Shows Promise In Targeting Leukemic Stem Cells." ScienceDaily. ScienceDaily, 28 December 2006. <www.sciencedaily.com/releases/2006/11/061117121634.htm>.
University of Texas M. D. Anderson Cancer Center. (2006, December 28). Experimental Drug Shows Promise In Targeting Leukemic Stem Cells. ScienceDaily. Retrieved September 17, 2014 from www.sciencedaily.com/releases/2006/11/061117121634.htm
University of Texas M. D. Anderson Cancer Center. "Experimental Drug Shows Promise In Targeting Leukemic Stem Cells." ScienceDaily. www.sciencedaily.com/releases/2006/11/061117121634.htm (accessed September 17, 2014).

Share This



More Health & Medicine News

Wednesday, September 17, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Obesity Rates Steady Even As Americans' Waistlines Expand

Obesity Rates Steady Even As Americans' Waistlines Expand

Newsy (Sep. 17, 2014) Researchers are puzzled as to why obesity rates remain relatively stable as average waistlines continue to expand. Video provided by Newsy
Powered by NewsLook.com
President To Send 3,000 Military Personnel To Fight Ebola

President To Send 3,000 Military Personnel To Fight Ebola

Newsy (Sep. 16, 2014) President Obama is expected to send 3,000 troops to West Africa as part of the effort to contain Ebola's spread. Video provided by Newsy
Powered by NewsLook.com
Obama Orders Military Response to Ebola

Obama Orders Military Response to Ebola

AP (Sep. 16, 2014) Calling the Ebola outbreak in West Africa a potential threat to global security, President Barack Obama is ordering 3,000 U.S. military personnel to the stricken region amid worries that the outbreak is spiraling out of control. (Sept. 16) Video provided by AP
Powered by NewsLook.com
UN: 20,000 Could Be Infected With Ebola by Year End

UN: 20,000 Could Be Infected With Ebola by Year End

AFP (Sep. 16, 2014) Nearly $1.0 billion dollars is needed to fight the Ebola outbreak raging in west Africa, the United Nations say, warning that 20,000 could be infected by year end. Duration: 00:40 Video provided by AFP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins