Fasting for two days protects healthy cells against chemotherapy, according to a study appearing online the week of Mar. 31 in PNAS Early Edition. Mice given a high dose of chemotherapy after fasting continued to thrive. The same dose killed half the normally fed mice and caused lasting weight and energy loss in the survivors.
The idea for the study came from the Longo group’s previous research on aging in cellular systems, primarily lowly baker’s yeast.
About five years ago, Longo was thinking about the genetic pathways involved both in the starvation response and in mammalian tumors.
When the pathways are silenced, starved cells go into what Longo calls a maintenance mode characterized by extreme resistance to stresses. In essence the cells are waiting out the lean period, much like hibernating animals.
But tumors by definition disobey orders to stop growing because the same genetic pathways are stuck in an “on” mode.
That could mean, Longo realized, that the starvation response might differentiate normal and cancer cells by their stress resistance, and that healthy cells might withstand much more chemotherapy than cancer cells.
The shield for healthy cells does not need to be perfect, Longo said. What matters is the difference in stress resistance between healthy and cancerous cells.
During the study, conducted both at USC and in the laboratory of Lizzia Raffaghello at Gaslini Children’s Hospital in Genoa, Italy, the researchers found that current chemotherapy drugs kill as many healthy mammalian cells as cancer cells.
“(But) we reached a two to five-fold difference between normal and cancer cells, including human cells in culture. More importantly, we consistently showed that mice were highly protected while cancer cells remained sensitive,” Longo said.
If healthy human cells were just twice as resistant as cancer cells, oncologists could increase the dose or frequency of chemotherapy.
“We were able to reach a 1,000-fold differential resistance using a tumor model in baker’s yeast. If we get to just a 10-20 fold differential toxicity with human metastatic cancers, all of a sudden it’s a completely different game against cancer,” Longo said.