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Source: Virginia Commonwealth University

Date: January 16, 2007

Researchers Develop New Method For Fighting Leukemia

Researchers at Virginia Commonwealth University's Massey Cancer

Center have created a new method to improve the antileukemic activity

of a novel agent that triggers programmed cell death, a development

that could lead to more effective strategies for fighting leukemia

and other malignancies.

The cell death process, or apoptosis, is characteristically impaired

in cancer cells. The process is regulated by a large family of

proteins that either promotes or inhibits cell death. Recently,

considerable attention has focused on the development of agents that

inhibit the actions of antiapoptotic members of this family.

One such agent, known as ABT-737, potently blocks the pro-survival

effects of two proteins, Bcl-2 and Bcl-xL, according to Grant,

M.D., Massey's associate director for translational research and co-

leader of the cancer center's cancer cell biology program. Grant is

senior author of the study, which is published in the Jan. 15 issue

of the journal Cancer Research.

In laboratory experiments, ABT-737 has been shown to be very

effective in killing tumor cells. However, this agent is unable to

block the actions of another anti-apoptotic family member, Mcl-1, and

it has been found that increased expression of Mcl-1 in tumor cells

significantly reduces the anti-tumor effectiveness of ABT-737.

Grant and colleagues demonstrated that interventions that reduce

levels of Mcl-1 in leukemia cells dramatically increase the

effectiveness of ABT-737. Specifically, they employed an agent called

roscovitine to block the synthesis of Mcl-1 at the RNA level. Grant

said that because Mcl-1 is a very short-lived protein, disrupting its

synthesis rapidly lowers Mcl-1 levels.

Grant's team found that the simultaneous reduction in Mcl-1

expression in conjunction with disruption of the anti-apoptotic

actions of Bcl-2 and Bcl-xL by ABT-737 resulted in the marked

activation of an important pro-apoptotic protein known as Bak. Grant

said that when Bak is freed from its constraints by these actions, it

cooperates with other pro-death proteins to induce mitochondrial

damage, culminating in the dramatic onset of apoptosis.

" Our findings are significant because we were able to employ

pharmacologic agents to recapitulate the death process that occurs in

normal cells, and which is impaired in their neoplastic

counterparts, " said Grant. " These findings could also have

significant translational implications for the treatment of leukemia

and potentially other malignancies. "

" For example, analogs of roscovitine have recently entered the

clinic, and a number of other agents capable of reducing Mcl-1 levels

in tumor cells are currently being developed, " he said.

Based upon the findings of Grant's group, regimens combining such

agents with Bcl-2 antagonists like ABT-737 could represent a

particularly effective treatment strategy in leukemia and various

other malignancies.

This work was supported by grants from the National Institutes of

Health, the Leukemia and Lymphoma Society of America, and the

Department of Defense.

Grant, a professor of medicine and the Shirley and Sture

Gordon Olsson Professor of oncology, worked with a team that

included: Shuang Chen, Ph.D., Yun Dai, Ph.D., and Hisashi Harada,

M.D., Ph.D., all in the VCU Department of Medicine; and Dent,

Ph.D., a professor in the VCU Department of Biochemistry.

Note: This story has been adapted from a news release issued by

Virginia Commonwealth University.