Biology in the News Explained

Starvation never felt so good

About a year ago, a medical paper came out that received surprisingly little attention in the media, despite its potentially profound ramifications for sufferers of chemotherapy (Raffaghello L, Lee C, Safdie FM, Wei M, Madia F, Bianchi G, Longo VD., 2008. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8215-20. Epub 2008 Mar 31).

Because cancer cells often proliferate rapidly, most of the nasty compounds cancer patients are given disrupt the process of cell division. But this makes traditional chemotherapy as (if not more) toxic to non-cancer cells as it is to cancer cells, which results in all the horrible “side-effects” associated with chemotherapy. Many of our normal cells divide rapidly as well, including those making up growing hair, lining the mouth and digestive tract, and most seriously, bone marrow producing white blood cells. Although hair loss and constant nausea are mostly just unpleasant, the low white cell counts associated with most chemotherapies can be life-threatening because they increase an often already-weakened patient’s susceptibility to infection.

The solution to these problems up to now has been the production of better anti-nausea drugs, and drugs that boost white cell production such as pegfilgrastim (Neulasta). Unforunately, these drugs have their own side effects. Neulasta users often experience a level of pain and suffering that makes the chemotherapy itself feel like a day on the beach.

So another research tack has been to do a better job targeting chemotherapy to cancer cells. If a drug could be designed that harms only cancer cells, cancer treatment would become a lot more pain free. This has been successful in isolated cases. For example, the drug trastuzumab (Herceptin) targets a special receptor found in some (not all) types of breast cancer, and essentially does not affect non-cancer cells. But in general, drugs this specific continue to be a Holy Grail, because there are so many types of cancer, each with widely varying pathologies from person to person. It may be that finding a general successful targeted treatment is as impossible as a cure for the common cold.

Raffaghello et al. hit on a different solution that not only could be highly effective, but also has the delightful benefit of paying out not one dime to the pharmaceutical industry – which, come to think of it, may be why the research received little publicity. The authors decided to approach the problem from the opposite direction: instead of trying to target chemotherapy so it only affects cancer cells, what if we find a way to protect normal cells from the drugs?

Some of the authors are gerontologists who study the relation between aging and metabolism, and they paired their knowledge of normal cell regulation to that of oncologists who understand cancer cell regulation. For decades, it has been known that “calorie restriction” (fasting) in many species extends lifespan; starvation induces stress resistance in normal cells. Other studies have suggested that calorie restriction can protect against cancer. The authors hypothesized that while normal cells respond to calorie restriction by entering a stress-resistance mode, cancer cells do not, because it has also been known for years that cancer cells are regulated more by oncogenes – genes activated in cancer cells – than by external factors, such as available nutrition.

The research was conducted both in isolated cells and in mice, and in both cases there were dramatic differences in the reaction to chemotherapy drugs between starved animals/cells and not: at high doses of the drugs, far more individuals survived when they had been starved before treatment. It appears then that their hypothesis was correct – short-term starvation causes normal cells, but not cancer cells, to become stress resistant. A probable mechanism of the stress resistance is that starving cells stop dividing, in order to save energy; because most chemotherapy drugs act on dividing cells, dormant cells are protected.

The beauty of this technique is that most people on chemotherapy receive drugs in 2-3 week cycles. The drugs are generally filtered out of the body within a few days. So theoretically, one need fast for only a few days before the treatment to receive the benefit.

Humans might need to fast for 3-4 days to achieve protective results. In one anecdote reported in the news section of Science (29 August 2008, 321:1146a-1147a), a human patient tried fasting for about 64 hours before treatment, and 24 hours after (to give time for the drugs to leave his system), and reported a large improvement in chemotherapy side effects.

The problem is that fasting this long would be difficult for many people, even if they know there will be benefits a couple of days later. Some other researchers offered an intriguing follow-up to the fasting study in their recent speculative paper (Johnson, J.B., John, S., and Laub, D.R. 2009. Pretreatment with alternate day modified fast will permit higher dose and frequency of cancer chemotherapy and better cure rates, Medical Hypotheses 72:381-382). Their goal was to figure out a fasting regime for chemotherapy patients that would have the same protective effects as fasting for 3-4 days, but be easier to stick to.

The authors tried a regime with mice in which they were starved on alternate days for 1, 2, 3, 4, or 6 weeks before a radiation treatment (which has similar effects as chemotherapy drugs). They found that the optimal period for this regime was 2-3 weeks. There are a couple benefits to this method. First, it should be easier for people to stay with an alternate-day-fast diet than to completely fast for 3 days in a row. Second, this diet maintains body weight at a more constant level, instead of the yo-yo effect that is found with the longer fasting followed by regular eating. Although their work is preliminary, the authors are currently planning a clinical trial to test this diet.

This could be a huge breakthrough in cancer treatment, because it could be that fasting people could tolerate higher doses of chemotherapy drugs, rendering the treatment more effective, while at the same time experiencing minimal inconvenient or life-threatening complications. It should finally be big news when the first results from human trials, already underway, are in.

As a final important note, at this time all researchers involved caution patients “do not try this at home!” because there have not yet been rigorous studies on humans to determine the effects, short- and long-term. Especially for those patients who have difficulty maintaining a healthy weight during chemotherapy, it could be dangerous to attempt a fasting regime. Above all, patients should always discuss any nontraditional treatment options they are considering with their doctors.


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  1. Cancer Research Carnival #21 - National Cancer Research Month | Highlight HEALTH - [...] to maximize the differential toxicity to normal and cancer cells [13]. Bioblog explains why Starvation Never Felt So Good ...

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