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Sunday, 13 April 2008 21:24

Experimental drug may block radiation damage

One dose of the early-stage experimental drug protected mice and monkeys from lethal doses of radiation. Future experiments will be conducted to see if tissues in humans can, likewise, be protected during radiation treatments and as an antidote from nuclear attacks.

Andrei V. Gudkov, who is chairperson of Cell Stress Biology within the Roswell Park Cancer Institute (Buffalo, New York, U.S.A.), was the lead researcher in the study.

The drug of interest has been named CBLB502, a polypeptide drug derived from Salmonella flagellin.

In the past and still today, radiation is a quite useful medical tool in combating diseases such as cancer by destroying cancerous cells. However, the radiation can also adversely affect healthy tissues, bone marrow, the gastrointestinal (GI) tract, and other such areas of the human body.

Because of the problems caused to normal cells, the amount and number of radiation treatments must be limited.

If this drug proves to be effective at protecting such healthy cells from radiation, it will be very important for future radiation treatments. However, other drugs have also been studied in the past, and they failed to live up to expectations.

The Gudkov team developed the drug related to the process called apoptosis. The process is the body’s natural (pre-programmed) way to stop defective cells from spreading to healthy cells. This activity called programmed cell death (PCD) occurs in all multicellular organisms.

However, apoptosis is prevented from occurring in cancer; that is, bad cells are killed but good cells are also adversely affected. Thus, it causes cancerous tumors to occur.

Gudkov and his team found that when apoptosis is prevented from occurring a pathway called “nuclear factor-KappaB” (NFKB) is also blocked.

The NFKB pathway is activated by flagellin, a protein in gut bacteria, and is normally used by apoptosis to destroy bad cells while leaving good cells alone.

Once the Gudkov team learned of the connection among apoptosis, NFKB, and flagellin, they decided to try to simulate the same pathway. Gudkov called their simulation a “tumor trick.” [Associated Press]

Consequently, they created a drug derived from the flagellin protein.

They injected the drug CBLB502 into mice and rhesus monkeys, waited from fifteen to sixty minutes, and then exposed the laboratory animals to lethal doses of radiation.

The investigators found that the drug improved survival rates, helping to protect bone marrow and the GI tract. The animals had more protection when the wait time was 60 minutes versus shorter times.

Especially important for radiation treatments for cancer patients, the drug CBLB502 did not prevent radiation from treating tumors in the mice as it protected healthy tissues.

As an added plus, the U.S. government is interested in the drug in order to protect its citizens against possible nuclear attack. Please read on for additional information. The abstract to the Gudkov paper is also included.

The U.S. Department of Defense (DoD) is especially interested in the applicability of the drug to possible nuclear attacks by terrorists.

Because of this use for biodefense, the DoD and other similar government agencies are funding the research by Gudkov.

In fact, Gudkov has founded the Cleveland, Biolab, Inc. to further develop the drug for possible introduction in the marketplace if it is found to be effective in humans and is approved for sale.

According to the Associated Press article “Drug Experiment Blocks Radiation Damage” by Lauran Neergaard, Dr. Richard Kolesnick (Memorial Sloan-Kettering Cancer Center, not associated with the study) stated, "For many years, the radiation oncology community has tried to develop radioprotectants. This new information on the mechanisms of tissue damage to the GI tract has resulted in a potentially important new drug to prevent this lethal GI syndrome after a radiation accident or potential terrorist attack."

The result of the researcher’s work is published in the April 11, 2008 issue of the journal Science. The title of the article is “An Agonist of Toll-Like Receptor 5 Has Radioprotective Activity in Mouse and Primate Models.”

Its authors are: Lyudmila G. Burdelya, Vadim I. Krivokrysenko, Thomas C. Tallant, Evguenia Strom, Anatoly S. Gleiberman, Damodar Gupta, Oleg V. Kurnasov, Farrel L. Fort, Andrei L. Osterman, Joseph A. DiDonato, Elena Feinstein, and Andrei V. Gudkov.

The abstract to their paper states, “The toxicity of ionizing radiation is associated with massive apoptosis in radiosensitive organs. Here, we investigate whether a drug that activates a signaling mechanism used by tumor cells to suppress apoptosis can protect healthy cells from the harmful effects of radiation.”

“We studied CBLB502, a polypeptide drug derived from Salmonella flagellin that binds to Toll-like receptor 5 (TLR5) and activates nuclear factor– B signaling. A single injection of CBLB502 before lethal total-body irradiation protected mice from both gastrointestinal and hematopoietic acute radiation syndromes and resulted in improved survival.”

“CBLB502 injected after irradiation also enhanced survival, but at lower radiation doses. It is noteworthy that the drug did not decrease tumor radiosensitivity in mouse models. CBLB502 also showed radioprotective activity in lethally irradiated rhesus monkeys. Thus, TLR5 agonists could potentially improve the therapeutic index of cancer radiotherapy and serve as biological protectants in radiation emergencies.”


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