Possible new use for Gleevec?

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Cancer Drug Slows Poxvirus in Mice

Mice given a relatively new cancer drug can survive an otherwise lethal dose

of vaccinia virus, a relative of smallpox virus, report scientists supported

by the National Institute of Allergy and Infectious Diseases (NIAID), part

of the National Institutes of Health. The findings, say the investigators,

suggest that Gleevec or similar drugs might be useful in preventing adverse

side effects of smallpox vaccine. The classic smallpox vaccine is made from

live, weakened vaccinia virus and is not recommended for people with

compromised immunity, except in emergency situations where they may have

been exposed to smallpox virus.

“This study helps illuminate the cellular machinery used by poxviruses to

exit infected cells, and also provides new support for the concept of

treating viral infections by targeting specific host cell molecules rather

than the viruses themselves,” says NIAID Director S. Fauci, M.D.

The senior author of the paper, published online this week in the journal

Nature Medicine, is Kalman, Ph.D., of Emory University School of

Medicine in Atlanta.

Like all viruses, poxviruses co-opt various cellular molecules and processes

to enter a cell, replicate and then spread to uninfected cells. Using lab-

grown cells, Dr. Kalman and his colleagues identified specific cell proteins

vaccinia uses to detach from an infected cell and move toward an uninfected

cell. The proteins, members of the Abl-family (pronounced “able”) of

tyrosine kinases, are well known to cancer investigators because mutation of

one family member, Abl, causes a rare form of cancer known as chronic

myelogenous leukemia (CML). Gleevec inhibits Abl-family tyrosine kinases and

has proved very useful in treating CML.

To learn whether Gleevec could prevent or lessen vaccinia’s ability to

spread in a living organism, the researchers treated mice with either saline

solution or with Gleevec at a dose equivalent to that given to humans being

treated for CML. Next, they exposed the mice to ordinarily lethal amounts of

vaccinia. All of the Gleevec-treated mice survived, while 70 percent of the

untreated mice died.

This finding, if confirmed in additional animal model studies, suggests that

Gleevec might play a role in addressing a public health emergency in the

event of a smallpox outbreak, Dr. Kalman says. Specifically, Gleevec might

be useful as a preventive against adverse effects of smallpox vaccine,

enabling clinicians to use the vaccine even in people who otherwise could

not take it. Given for a short period, Gleevec theoretically could hamper

the cell-to-cell spread of virus and allow the body’s immune system to mount

a successful defense, he explains. Experiments to test whether Gleevec might

work against smallpox virus as well as against vaccinia virus are now being

planned, Dr. Kalman says. “The approach of fighting disease by targeting

drugs to cellular molecules rather than to disease agents themselves may be

applicable to a wide variety of pathogenic microorganisms,” he says.

Routine vaccinations for smallpox ended in this country in the early 1970s,

and the World Health Organization declared smallpox eradicated in 1980.

Nevertheless, concern remains that smallpox virus could be unleashed through

an act of bioterror. For this reason, scientists are working to better

understand the mechanisms of smallpox disease and to develop new and

improved smallpox treatments and vaccines.

NIAID is a component of the National Institutes of Health, an agency of the

U.S. Department of Health and Human Services. NIAID supports basic and

applied research to prevent, diagnose and treat infectious diseases such as

HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis,

malaria and illness from potential agents of bioterrorism. NIAID also

supports research on transplantation and immune-related illnesses, including

autoimmune disorders, asthma and allergies.

News releases, fact sheets and other NIAID-related materials are available

on the NIAID Web site at http://www.niaid.nih.gov.

The National Institutes of Health (NIH) — The Nation's Medical Research

Agency — is comprised of 27 Institutes and Centers and is a component of the

U. S. Department of Health and Human Services. It is the primary Federal

agency for conducting and supporting basic, clinical, and translational

medical research, and investigates the causes, treatments, and cures for

both common and rare diseases. For more information about NIH and its

programs, visit www.nih.gov.

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Reference: PM Reeves et al. Disabling poxvirus pathogenesis by inhibition of

Abl-family tyrosine kinasas. Nature Medicine DOI: 10.1038/nm1265 (2005).