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Fasting increased efficacy of chemotherapy in mice
Lee C. Sci Transl Med. 2012;doi:10.1126/scitranslmed.3003293.
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The combination of multiple cycles of starvation and chemotherapy was linked to increased efficacy of drugs used to treat various cancers, according to study results published in Science Translational Medicine.
Fasting combined with chemotherapy improved survival and slowed tumor growth and/or limited the spread of tumors in all cancers tested, researchers said. Fasting alone also slowed the spread and growth of five of eight cancers tested in mice, including transplanted cancer tumors made of human cells, researchers found.
“Fasting protects mice and, possibly, humans against a range of chemotherapy drugs,” Valter D. Longo, PhD, professor of gerontology at the University of California Davis School of Gerontology, told HemOnc Today. “We show in mouse models that it sensitizes a wide range of mouse and human cancer/cancer cell types to chemotherapy. In several cases, it works as well as chemotherapy.”
A determination of whether humans would benefit from the same treatment would require a clinical trial lasting several years, Longo said.
He and colleagues conducted the study on the hypothesis that short-term starvation, or fasting, protects normal cells in mice from adverse events associated with a range of chemotherapy drugs.
The study results demonstrated that fasting conditions sensitized yeast cells (Saccharomyces cerevisiae) expressing the oncogene-like RAS2val19 to oxidative stress from chemotherapy. Fifteen of 17 mammalian cancer cell lines also were linked to an increased sensitization to chemotherapy by fasting.
Further results indicated that cycles of fasting were as effective as chemotherapy in delaying progression of specific tumors. Chemotherapy drugs used to fight melanoma, glioma and breast cancer cells were more effective when cycles of starvation were used.
The combination of fasting cycles plus chemotherapy was linked to long-term DFS in mouse models of neuroblastoma. However, neither fasting nor chemotherapy alone had the same outcomes.
“The clinical trials and case studies indicate that fasting for up to 72 hours in combination with chemotherapy is safe,” Longo said, adding that it may not be suitable for patients with diabetes or those who already have lost more than 10% of their body weight.
Fasting also was associated with increased phosphorylation of the stress-sensitizing AKT and S6 kinases, increased oxidative stress, caspase-3 cleavage, DNA damage and apoptosis in 4T1 breast cancer cells.
The findings suggest that multiple cycles of fasting promote differential stress sensitization in a wide range of tumors, according to the researchers.
“The take-home message for oncologists should be to consider it and decide whether, based on each specific case and the options available, it is reasonable to suggest fasting to the patient before clinical trials are completed,” Longo said.
Disclosure: Dr. Longo founded L-Nutra, a company that will sell substitution diets to support cancer patients receiving treatment.
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These are fascinating and rigorous studies that evoke many hypotheses. Many years ago, chronobiologists attempted to interest oncologists in the notion that the time of day chemotherapy is administered might significantly affect therapeutic indices. Some exuberant claims were published but generally ignored. The possibility that altered glucose, insulin growth factors and the like — which are fine-tuned to nutrition — may sensitize neoplastic (but not normal) cells to toxic effects of chemotherapeutic agents would seem worth a new look. There are many examples of paradoxical beneficial effects of nutritional deficiency that can rapidly and unfortunately become harmful with refeeding.
In the hematologic arena, two of many examples can be cited: (A) the devastating bacterial infections that not infrequently follow vitamin B12 repletion in pernicious anemia patients; and (B) the intriguing syndrome of “refeeding malaria” in mosquito-bereft locales such as sub-Saharan Africa. In the latter, my colleagues and I (Eaton JW. Nature. 1976;264:758-760) demonstrated that starvation-associated deficiency of the antioxidant vitamin E protected nomadic tribesman from falciparum malaria by promoting oxidant-mediated premature hemolysis of infected red cells, thereby interrupting the parasite's life cycle. Upon being provided vitamin E-rich grains in refeeding stations, previously-latent, and often fatal, malaria occurs. This ironic scenario was validated in mouse studies and, with the studies reviewed above, may diminish the cynicism of some if they consider fasting patients prior to provoking more fasting with their chemotherapy.
Harry S. Jacob, MD, FRCPath (Hon)
HemOnc Today Chief Medical Editor
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