Alternate day modified fast 4 cancer chemotherapy?

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Hi All,

Will an alternate day modified fast provide optimum cancer chemotherapy outcomes? The below paper is pdf-availed, and its free full-text (9) reference paper may provide background information well.

9. Raffaghello L, Lee C, Safdie FM, Wei M, Madia F, Bianchi G, Longo VD.Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy.Proc Natl Acad Sci U S A. 2008 Mar 31. [Epub ahead of print]PMID: 18378900 http://tinyurl.com/7uw4cjhttp://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed & pubmedid=18378900

Pretreatment with alternate day modified fast will permit higher dose and frequency of cancer chemotherapy and better cure rates. JB, S, Laub DR.Med Hypotheses. 2009 Jan 8. [Epub ahead of print]PMID: 19135806

Summary

It is established that calorie restriction (CR) increases the resistance of cells to various stressors such as oxidative damage, excitotoxins, mercury and acetaminophen. Alternate day feeding (ADF) may confer greater stress resistance than daily CR of 30% or 40%.

A recent study in three strains of mouse showed that a fast of 48 or 60 h prevented toxic effects due to administration of doses 2–4 times the maximum human dose of etoposide, a chemotherapy agent which acts through increased oxidative stress. In addition, mice inoculated with neuroblastoma survived longer when pretreated with fasting, then given high dose etoposide, as well as not exhibiting toxicity. This increased survival was construed as evidence of differential stress resistance between normal and cancer cells, the cancer cells being only partially protected by the pretreatment fast.

In clinical practice, increased differential stress resistance could lead to the use of much higher doses of chemotherapy agents, and in the absence of toxicity, make it possible to repeat the treatment to kill residual cancer cells. Humans are unlikely to comply with a total fast of longer than 24 or 48 h, which may be insufficient to activate the same gene expression process.

Based on published data we estimate that an optimal time period for development of stress resistance is 2–3 weeks when alternate day feeding is employed. Our previously published experience suggests that 2–3 weeks of alternate day modified fast in which subjects eat ad libitum one day and <20% of one’s estimated caloric requirement the next will confer a similar stress resistance. Compliance with this diet is high and greater maintenance of body weight is feasible. We hypothesize that a pretreatment of 2–3 weeks with the alternate day modified fast will improve outcomes in cancer chemotherapy, decreasing morbidity and raising cure rates.

We hypothesize that cancer chemotherapy and radiation therapy dosing can be increased in patients pretreated for 2–3 weeks with an alternate day modified fast. By increasing differential stress resistance between normal cells and cancer cells, systemic toxicity can be minimized and improve treatment outcomes.

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Daily calorie restriction (CR) of 30–40% and alternate day feeding (ADF) [1], [2] and [3] prolongs lifespan and delays the onset of age related diseases in rodents and other animals [4], [5] and [6]. Among the cellular functions which mediate these effects via hormesis is an increase in resistance to various stressors including oxidative damage [5]. In animals subjected to daily CR or alternate day feeding, cells exhibit increased resistance to a range of toxins including neurotoxins, carcinogens, mercury and ionizing radiation [7] and [8].

Recently Raffaghello et al. [9] showed that short term starvation (STS) of 48 and 60 h increased resistance to oxidative stress in yeast and greatly reduced the toxicity of high doses of a chemotherapy drug in three different strains of mice. Fasted mice survived without apparent toxic effects despite receiving 2–3 times the maximum human dose of etoposide, which acts by oxidative injury to DNA. Over 40% of control mice receiving this high dose died and the survivors exhibited severe toxicity.

In one part of the study mice were starved for 48 h and given a dose of etoposide 3 times greater than the maximum used in humans. Forty three percent of control (non-starved) mice died while only one of the pre-starved mice died. The starved mice lost 20% of their weight in 48 h and regained most of it in the 4 days after chemotherapy while control mice lost 20% of their weight after treatment. The starved mice recovered completely but the surviving controls showed signs of toxicity including poor mobility, hunched back and ruffled hair.

A second group was fasted for 60 h and given 4–5 times the maximum human dose. All of the control mice died by day 5 but none of the fasted mice died or showed signs of toxicity. The fasted group lost 40% of its weight in 60 h, but regained it in 1 week, whereas the surviving control mice lost 20–30% of their body weight after treatment and showed marked signs of toxicity.

A third group of mice injected with neuroblastoma-type malignant cells survived longer than controls and showed no signs of toxicity from the same high dose of etoposide. This longer survival indicated a higher kill ratio of malignant cells and the authors suggest that the absence of toxicity using much higher than normal dose chemotherapy might make it feasible to use multiple treatments to kill most or all cancer cells. This could lead to higher cure rates.

Many caloric restriction scientists are of the opinion that the slowing of aging and protection from disease requires long term CR and that alternate day calorie restriction could improve health only if a net weight loss occurs. This is supported by evidence that lower body fat is correlated with longer lifespan. However, Raffaghello et al. suggests that profound resistance to oxidative damage can be induced by fasting for 48 h, yet body weight returned to normal upon refeeding.

The observed cellular events may be due to down-regulation of Akt, Ras, and other proto-oncogenes in response to reduction in IGF-1 and other growth factor levels caused by the starvation [10]. This reduces growth and promotes protection to chemotherapy. Tumor cells respond only partially to starvation and are therefore only partially protected from high dose chemotherapy.

This study is also important because it shows how rapidly the protective maintenance of the CR mechanism is activated by total fasting, which may be seen as more intense stimulus to the CR stress response than reducing daily calories chronically by 30–40%. Mattson and colleagues showed that ADF reduced neuronal injury more than did a 40% daily reduction in calories in a mouse model in which an excitotoxin (keinic acid) was injected into the hippocampus. The same investigators have shown that artificial ischemic injury in mouse heart and brain is markedly reduced by ADF.

Other evidence suggests that the period of fasting to produce optimal stress resistance may be longer in humans than would be acceptable to most people. A fast of 24–48 h may be insufficient and longer fasts would probably be rejected by patients. However, we believe that alternate day calorie restriction may offer the solution. We have studied a pattern of eating in which every other day calories are restricted to 20% of normal requirement and on the intervening days, subjects eat ad libitum.

The stress resistance from CR is likely to be part of a unified gene expression response to low energy supply possibly initiated by SIRT1 activation. In our study of the effect on asthma of alternate day calorie restriction, there were improvements in oxidative stress markers, inflammatory markers and clinical findings which started almost immediately but improved rapidly, reaching a plateau at around 3 weeks [11]. Peak expiratory flow (PEF, an index of small airway inflammation), quality of life questionnaires and subjective mood/energy rating also followed this temporal pattern. The mood/energy rating might reflect CNS stress resistance.

We hypothesize that the gene expression response is a dose related process; each 36 h period (from after dinner until breakfast of the day after tomorrow) of <20% of normal calories activates this CR mechanism. This may be by formation of a protein, e.g. SirT1, which persists for several days and with each successive 36 h period a higher titer is achieved until a maximum concentration is reached at which point a steady state of creation and decay of SirT1 is present. Based on our study, 2–3 weeks of ADD is needed to reach this steady state. If there is a correlation between development of stress resistance and our findings of improved clinical and biochemical parameters, then near maximal stress resistance would take around 3 weeks to develop.

In a study in which mice were pre-treated with alternate day feeding then exposed to lethal doses of whole body ionizing radiation, the survival rate was up to four times greater than controls [12]. The most effective period of pretreatment was 2–3 weeks (Fig. 1).

It seems highly likely that a total fast for a period of several days would do the same thing, but from our findings, we doubt that a 48 h fast will confer maximal protection. Most humans hate the idea of total fasting whereas our experience has been that the alternate day diet (ad lib/20%) is acceptable to motivated individuals. Concerns about inadequate nutrition in patients with cancer might contra-indicate prolonged fasting whereas the alternate day diet might maintain body weight.

We are planning a clinical trial using a 2 week period of alternate day diet followed by dosing with chemotherapy drugs which work via oxidative damage.

-- Al Pater, alpater@...