A new drug may protect healthy tissue during cancer-killing radiation treatments or other exposures. Molecular geneticist Andrei Gudkov and colleagues report in Science this week that they protected mice from the cell-damaging effects of radiation by injecting them with a compound that helps cells resist apoptosis, or self-destruction.
Previous studies have found that cancerous cells use nuclear factor kappa-beta--a transcription factor, or protein that turns on or off a gene's protein-making ability--to outlive normal cells and grow out of control. But healthy cells in the gut switch on the same transcription factor when they interact with benign and beneficial bacteria that reside there. Specifically, the protein flagellin in some of the microorganisms' whiplike tails (which they use for propulsion) binds with a receptor on the gut cell and triggers the production of the transcription factor.
So, in an effort to steel healthy cells against radiation damage, Gudkov, chairman of the cell stress biology department at Roswell Park Cancer Institute in Buffalo, N.Y., and his colleagues purified a batch of flagellin and injected it into mice 30 minutes before exposing them to lethal doses of radiation.
The injection not only protected the mice's cells but also toughened them against the effects of free radicals (molecules that can damage DNA or genetic material inside them) as well as beefed up the animal's immune systems. Mice without the injection died after the radiation treatments. "Never before has a single agent been capable of doing all three things together," Gudkov says.
The researchers then produced a drug called CBLB502 that was designed to mimic flagellin; it protected 87 percent of the mice from lethal doses and also safeguarded against free-radical damage.
They found that the drug only worked if injected within an hour prior to exposure to high levels of radiation. It also showed some protective effects if injected after exposure to lower levels.
The drug did not, however, appear to protect malignant cells from the radiation treatments designed to kill them. Gudkov says that in addition to mice, researchers have also tested several dozen human tumor cell lines and "could not find a single one that benefited" from the drug.
That means the drug, also known as Protectan, could be used, if proved safe in further testing, to protect patients undergoing bone marrow transplants or cancer treatments involving radiation. It could also be given in the event of a nuclear explosion or meltdown. "We envision people carrying preloaded, self-administrable syringes loaded with the compound ready for immediate intramuscular injection," Gudkov says. "It would be given to military and first responders first and, then, why wouldn't it be available to everybody?"
The U.S. Department of Defense has already signed a contract with Gudkov's Buffalo-based company, Cleveland BioLabs, Inc., to develop the drug as a radiation countermeasure. Human safety tests are set to begin in a few months but will take several years to complete. "Based on monkey and mice studies, we do not expect any severe side effects," Gudkov says.
"The final proof will be empirical testing in large numbers of people. But we're fairly confident that we are dealing with something pretty safe."