One of the ironies of cancer is that patients generally feel worse after treatment than before; radiation and chemotherapy induce widespread cell death, by activating the DNA damage response via p53.

P53's claim to fame is that it is a tumor suppressor, and so conventional wisdom holds that you can't make an omelet without breaking eggs: Chemotherapy's and radiation's side effects are "generally deemed an unfortunate but unavoidable consequence of the role p53 has in tumor suppression," a research team from the University of California at San Francisco wrote in the Sept. 7, 2006, issue of Nature.

But in its paper, the team presented data that suggested it might be possible to separate the baby from the bathwater, preventing radiation-induced p53 activation from bumping off cells left and right in response to DNA damage while preserving the protein's cancer-suppressing ability.

The scientists suspected that p53's tumor suppression might not be dependent on the DNA damage response because most DNA damage does not, in fact, cause cancer; senior author Gerard Evan likened using the DNA damage response for tumor suppression to "using a hammer to crack eggs."

Mice lacking p53 take months to develop tumors, despite not having a DNA damage response. And when they do, the tumors arise from a single cell, out of the millions that have had DNA damage in the interim. So "almost every cell that gets damaged does not form a tumor," Evan told BioWorld Today.

"P53 clearly didn't evolve as a cancer suppressor," said Evan, who is a professor of cancer biology at UCSF. The protein appeared early in evolution, in organisms that had neither the size nor the longevity that make it possible to develop cancer in the first place; Evan said that during the course of evolution, p53 may have been hijacked from its original role, so that "our tumor-suppressor response and our DNA-damage response are now routed through the same engine. That's the way it is, but that's not the way it has to be."

To test whether P53's tumor-suppressor abilities could be separated from its DNA-damage response, the researchers irradiated three groups of mice, with a dose that Evans said was similar to that received by the victims of the Hiroshima and Nagasaki bombs. The animals were then checked for damage due to the irradiation, and for the occurrence of tumors down the road.

All animals had a mutated version of p53 that was not normally responsive to DNA damage signals but could be rendered responsive to normal by a drug, though the drug itself did not activate the p53. One group never had p53 function restored; another group had p53 function restored for six days immediately prior to and during the irradiation; and a third group had no p53 function during the irradiation, but had p53 function restored a week later.

Mice with no functional p53 at any time did not show radiation-induced sickness, but did start developing tumors by about 4 months of age; none of the animals survived beyond about 10 months of age. (The maximal lifespan of nonirradiated p53 knockouts is about 12 months.)

Mice whose p53 function was restored during irradiation were in the worst shape; they developed radiation sickness including damaged intestinal lining and low white blood cell count. But their brief spell of p53 did not protect them from cancer; they started developing tumors, and died from them, at a rate that was indistinguishable from the group with no active p53.

In contrast, mice with p53 function restored one week after irradiation were comparatively lucky: Not only did they not suffer radiation sickness, but they developed tumors, on the average, about 100 days later than their p53 knockout brethren.

To investigate exactly how delayed p53 activation protects mice from radiation-induced cancer, the researchers next created inducible p53 animals that also lacked P19ARF protein. P19ARF activity "only occurs in cells with oncogenic mutations due to DNA damage," Evans explained, making it a likely candidate to activate p53. And indeed, P19ARF-deficient animals did not benefit from delayed p53 restoration.

The data suggested that if timing issues can be worked out, it might be possible to make cancer treatment less of an ordeal by briefly inhibiting p53 during chemotherapy or radiation. Such inhibition is advocated by some physicians, but the concern has been that by inhibiting p53, "you may just be storing up cancer for the future," Evan said. "Eventually, all the mice came down with cancer. So we're not giving as good protection as if we were keeping [p53] on all the time." Wild-type mice will rarely develop tumors and will live for two to three years.

But given that six days of p53 activation led to a delay in tumor formation of more than three months, a brief inactivation is not outside the realm of possibilities.

On the futuristic side, turning the body's relationship to p53 into an on-again, off-again pattern might have other uses as well.

"You can have all the benefits of a p53-negative lifestyle. You can go to a nuclear reactor, you can go to Mars, you might even age more slowly," since p53 activation also plays a role in the aging process. "And as long as you restore p53 intermittently, you can clean out incipient cancers."

The latter possibilities are "very, very speculative," Evan cautioned. "But it's certainly not inconsistent with our data."