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The old adage "feed a cold, starve a fever" may need be updated to feed a cold, starve a fever—and kill a tumor.
Scientists at the University of Southern California (along with Italian researchers) report today that fasting for 48 hours before receiving chemotherapy could help limit the treatment's toxic effects to cancer cells—and spare healthy ones. The new finding may pave the way for higher and more frequent chemo doses that better shrink tumors without harming normal cells.
The technique stems from lessons learned during research on aging, according to Valter Longo, a U.S.C. gerontologist and co-author of the new study published in Proceedings of the National Academy of Sciences USA: When normal cells are starved, the body uses up stores of glucose and energy to keep them functioning; in response, the cells shift into survival mode, revving up repair mechanisms and protective processes to resist anything—including potentially fatal drugs—that threaten to damage their genetic material.
"You can think of it as something similar to the fight-or-flight system," he says. "When you have a dog running after you, the system redirects towards the muscles for running, for instance, and away from the immune system and other normal processes."
Longo hatched the starvation trick based on his research showing that restricting calories may increase life span. Working with baker's yeast, he and other researchers found that the fungus sustains less cellular damage as it ages when deprived of key nutrients, allowing it to live longer. Mammalian cells have a version of the genetic pathway that controls this starvation response in yeast. So, Longo decided to exploit a key difference between normal cells and cancerous ones: In tumor cells, these genetic pathways are essentially disabled because the cells are programmed solely to grow and divide. Thus, starving an organism may trigger normal cells to put up their guard, leaving cancer cells to absorb chemotherapy agents.
Indeed, the team found that the chemo drugs were more effective at killing tumor cells, although they left normal cells unharmed. In yeast injected with cancerous cells, for instance, the research team was able to get a chemotherapy agent to knock out 1,000 cancer cells for every one normal cell, compared with a normal one-to-one ratio
In an effort to get a handle on toxicity, researchers starved mice (injected with malignant cells) before giving them megadoses of chemo; the animals lost up to 40 percent of their weight but regained it—and their energy—once treatment ended. What's more, Longo says, the therapy—three times that considered to be a high human dose—also did not appear to have any toxic side effects. In contrast, when mice on normal diets were given cancer and chemo, they were sapped of energy, did not gain back lost weight, and died much sooner than their fasting peers.
Longo estimates that healthy cells in starving mice were five to 10 times more resistant than cancer ones to chemotherapy. "If we can get to 20- or 50-fold," he says, "we are in a very different position in the fight against in cancer."
He's optimistic that researchers can attain that goal with a combination of limited fasting and drugs that kill malignant cells but also prod healthy ones to up their defenses.
Felipe Sierra, a cell biologist at the National Institute on Aging, praised the effort as a new way of attacking cancerous cells by steeling normal ones against the ill effects of chemo (rather than trying to only target malignancies, which is difficult to do). He cautioned that it would only work in patients robust enough to endure two days of fasting before chemotherapy, but noted that many of them are up to task.
But James Harper, a pathologist at the University of Michigan School of Medicine, is skeptical, noting that in some cases mice given chemo and food actually outlived their starved brethren. "It's probably a little too early to start jumping up and down" he says, "touting this as a new way to treat cancer."
Longo agrees that although the technique is not quite ready for prime time, it offers the promise of better treatment. He plans to begin clinical trials to test its effectiveness in humans within six months.
