To Fast or not to Fast….

Fasting

At my Oncology follow-up appointments, I generally ask if there is anything new on the horizon. Last time I asked about fasting – the reason – well I had just finished a fantastic book about fasting for health:

https://www.amazon.co.uk/Complete-Guide-Fasting-Intermittent-Alternate-Day-ebook/dp/B01MF8SC2X

How to do fasting in intricate detail – but it can be tough so so always consult an expert… (and I am not one of those having received next to no training on nutrition at medical school!!)

My oncologist considered that fasting was interesting in theory but he was concerned about the effects of fasting on frail patients undergoing intensive chemotherapy and also the lack of clinical trial data.

Fasting seems to be very “buzz” and my interest was piqued last year when I espied a paper from Newcastle University describing the use of ultra low calorie diets to reverse type 2 diabetes. And the initial studies do suggest that a 2 month lifestyle change to an ultra low calorie diet can infact reverse type 2 diabetes if caught in the early stages… This is MASSIVE!

http://www.diabetes.co.uk/news/2016/oct/itv-tonight-programme-explores-reversal-of-type-2-diabetes-through-diet-93113859.html

http://www.directclinicaltrial.org.uk

Looking into this subject further revealed a researcher named Valter Longo who is the current Edna M Jones Professor of Gerontology at USC Davis.

http://gero.usc.edu/faculty/longo/

This intrepid researcher boasts a huge list of publications investigating fasting, longevity, cancer etc. The research started as basic science in rodents but is now moving forward into the clinical trial arena. Indeed some of the research is now hitting the press and social media:

https://news.usc.edu/118758/fasting-during-chemotherapy-may-offset-spikes-in-blood-sugar-caused-by-cancer-fighting-drugs/

https://news.usc.edu/103972/fasting-like-diet-turns-the-immune-system-against-cancer/

Of note Longo does admit that fasting is tough and perhaps for that reason he has devised a fasting-mimicking diet plan to achieve the same ends with a more patient-friendly method. This method involves a 5 days per month of dietary restriction to 700-1100 calories.

Fasting, at least in rodents seems to work by reducing blood glucose levels and levels of the important growth factor IGF-1 (Insulin like growth factor). This effect may be beneficial in a number of chronic diseases like cancer and cardiovascular disease, not to mention type 2 diabetes. Early studies in humans are promising but Longo cautions that patients should not try this at home without medical supervision.

Summarising – fasting seems to have profound benefits for weight loss in obesity and type 2 diabetes and that is just for starters. Benefits in cancer and heart disease in human need further study.

Mice lose weight and live longer

Sugar and insulin levels fall in both rodents and humans. Immune function is improved.

IGF-1 levels fall

Mice seem to develop less tumours when fasted

Fasting around chemo seems to be safe in small clinical studies

Fasting may sensitise tumours to chemotherapy (i.e the response is greater)

Side effects of chemotherapy may be reduced by intermittent or periodic fasting

Fasting in combination with other integrative approaches such as herbal medicine is under investigation

Will I try fasting if I am offered second-line chemo in the future? Well I don’t want to lose weight – I have lost 20kg over the last 3 years – mainly dietary. My weight is stable but I’m not sure. The theory sounds great but I need to see more success stories and clinical trials using this approach.

If interested, below are summarised some of Valter Longo’s major papers:

Di Biase et al 2017

PLoS Biol. 2017 Mar; 15(3): e2001951.

Published online 2017 Mar 30. doi:  10.1371/journal.pbio.2001951

Fasting reduces glucose levels and protects mice against chemotoxicity, yet drugs that promote hyperglycemia are widely used in cancer treatment. Here, we show that dexamethasone (Dexa) and rapamycin (Rapa), commonly administered to cancer patients, elevate glucose and sensitize cardiomyocytes and mice to the cancer drug doxorubicin (DXR). Such toxicity can be reversed by reducing circulating glucose levels by fasting or insulin. Furthermore, glucose injections alone reversed the fasting-dependent protection against DXR in mice, indicating that elevated glucose mediates, at least in part, the sensitizing effects of rapamycin and dexamethasone. In yeast, glucose activates protein kinase A (PKA) to accelerate aging by inhibiting transcription factors Msn2/4. Here, we show that fasting or glucose restriction (GR) regulate PKA and AMP-activated protein kinase (AMPK) to protect against DXR in part by activating the mammalian Msn2/4 ortholog early growth response protein 1 (EGR1). Increased expression of the EGR1-regulated cardioprotective peptides atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in heart tissue may also contribute to DXR resistance. Our findings suggest the existence of a glucose–PKA pathway that inactivates conserved zinc finger stress-resistance transcription factors to sensitize cells to toxins conserved from yeast to mammals. Our findings also describe a toxic role for drugs widely used in cancer treatment that promote hyperglycemia and identify dietary interventions that reverse these effects.

Impact of intermittent fasting on health and disease processes

Mark P. Mattsona, b, , , Valter D. Longoc, Michelle Harvied

http://doi.org/10.1016/j.arr.2016.10.005

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Mattson et al. 2016

Ageing Research Reviews

Abstract

Humans in modern societies typically consume food at least three times daily, while laboratory animals are fed ad libitum. Overconsumption of food with such eating patterns often leads to metabolic morbidities (insulin resistance, excessive accumulation of visceral fat, etc.), particularly when associated with a sedentary lifestyle. Because animals, including humans, evolved in environments where food was relatively scarce, they developed numerous adaptations that enabled them to function at a high level, both physically and cognitively, when in a food-deprived/fasted state. Intermittent fasting (IF) encompasses eating patterns in which individuals go extended time periods (e.g., 16–48 h) with little or no energy intake, with intervening periods of normal food intake, on a recurring basis. We use the term periodic fasting (PF) to refer to IF with periods of fasting or fasting mimicking diets lasting from 2 to as many as 21 or more days. In laboratory rats and mice IF and PF have profound beneficial effects on many different indices of health and, importantly, can counteract disease processes and improve functional outcome in experimental models of a wide range of age-related disorders including diabetes, cardiovascular disease, cancers and neurological disorders such as Alzheimer’s disease Parkinson’s disease and stroke. Studies of IF (e.g., 60% energy restriction on 2 days per week or every other day), PF (e.g., a 5 day diet providing 750–1100 kcal) and time-restricted feeding (TRF; limiting the daily period of food intake to 8 h or less) in normal and overweight human subjects have demonstrated efficacy for weight loss and improvements in multiple health indicators including insulin resistance and reductions in risk factors for cardiovascular disease. The cellular and molecular mechanisms by which IF improves health and counteracts disease processes involve activation of adaptive cellular stress response signaling pathways that enhance mitochondrial health, DNA repair and autophagy. PF also promotes stem cell-based regeneration as well as long-lasting metabolic effects. Randomized controlled clinical trials of IF versus PF and isoenergetic continuous energy restriction in human subjects will be required to establish the efficacy of IF in improving general health, and preventing and managing major diseases of aging.

BMC Cancer. 2016; 16: 360.

Published online 2016 Jun 10. doi:  10.1186/s12885-016-2370-6

PMCID: PMC4901417

Safety and feasibility of fasting in combination with platinum-based chemotherapy

Tanya B. Dorff, Susan Groshen, Agustin Garcia, Manali Shah, Denice Tsao-Wei, Huyen Pham, Chia-Wei Cheng, Sebastian Brandhorst, Pinchas Cohen, Min Wei, Valter Longo,pastedGraphic.png and David I. QuinnpastedGraphic.png

Author information ► Article notes ► Copyright and License information ►

.

Abstract

Background

Short-term starvation prior to chemotherapy administration protects mice against toxicity. We undertook dose-escalation of fasting prior to platinum-based chemotherapy to determine safety and feasibility in cancer patients.

Methods

3 cohorts fasted before chemotherapy for 24, 48 and 72 h (divided as 48 pre-chemo and 24 post-chemo) and recorded all calories consumed. Feasibility was defined as ≥ 3/6 subjects in each cohort consuming ≤ 200 kcal per 24 h during the fast period without excess toxicity. Oxidative stress was evaluated in leukocytes using the COMET assay. Insulin, glucose, ketones, insulin-like growth factor-1 (IGF-1) and IGF binding proteins (IGFBPs) were measured as biomarkers of the fasting state.

Results

The median age of our 20 subjects was 61, and 85 % were women. Feasibility criteria were met. Fasting-related toxicities were limited to ≤ grade 2, most commonly fatigue, headache, and dizziness. The COMET assay indicated reduced DNA damage in leukocytes from subjects who fasted for ≥48 h (p = 0.08). There was a non-significant trend toward less grade 3 or 4 neutropenia in the 48 and 72 h cohorts compared to 24 h cohort (p = 0.17). IGF-1 levels decreased by 30, 33 and 8 % in the 24, 48 and 72 h fasting cohorts respectively after the first fasting period.

Conclusion

Fasting for 72 h around chemotherapy administration is safe and feasible for cancer patients. Biomarkers such as IGF-1 may facilitate assessment of differences in chemotherapy toxicity in subgroups achieving the physiologic fasting state. An onging randomized trial is studying the effect of 72 h of fasting.

Version 1. F1000Res. 2016; 5: F1000 Faculty Rev-117.

Published online 2016 Jan 29. doi:  10.12688/f1000research.7136.1

PMCID: PMC4755412

Dietary restriction with and without caloric restriction for healthy aging

Changhan Leea,1 and Valter Longob,1,2

Author information ► Article notes ► Copyright and License information ►

This article has been cited by other articles in PMC.

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Abstract

Caloric restriction is the most effective and reproducible dietary intervention known to regulate aging and increase the healthy lifespan in various model organisms, ranging from the unicellular yeast to worms, flies, rodents, and primates. However, caloric restriction, which in most cases entails a 20–40% reduction of food consumption relative to normal intake, is a severe intervention that results in both beneficial and detrimental effects. Specific types of chronic, intermittent, or periodic dietary restrictions without chronic caloric restriction have instead the potential to provide a significant healthspan increase while minimizing adverse effects. Improved periodic or targeted dietary restriction regimens that uncouple the challenge of food deprivation from the beneficial effects will allow a safe intervention feasible for a major portion of the population. Here we focus on healthspan interventions that are not chronic or do not require calorie restriction.

Keywords: Caloric restriction, mechanisms of aging, Dietary restriction, aging, healthspan

Semin Cancer Biol. Author manuscript; available in PMC 2016 Dec 1.

Published in final edited form as:

Semin Cancer Biol. 2015 Dec; 35(Suppl): S276–S304.

doi:  10.1016/j.semcancer.2015.09.007

PMCID: PMC4819002

NIHMSID: NIHMS754223

A Broad-Spectrum Integrative Design for Cancer Prevention and Therapy

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Abstract

Targeted therapies and the consequent adoption of “personalized” oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity “broad-spectrum” therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested; many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to help us address disease relapse, which is a substantial and longstanding problem, so a proposed agenda for future research is offered.

Fontana et al. 2012

Growth Factors, Nutrient Signalling, and Cardiovascular Ageing

http://circres.ahajournals.org/content/110/8/1139

Growth factors regulated by specific macronutrients have been shown to promote aging and accelerate mortality in the majority of the organisms studied. In particular, the enzymes activated by growth hormone, insulin, and insulin-like growth factor-1 in mammals and their orthologs in simple model organisms represent perhaps the best-understood proteins involved in the aging process. Dietary restriction, which reduces the level of insulin-like growth factor-1 and of other growth factors, has been associated with protection from diabetes, cancer, and cardiovascular diseases, and deficiencies in growth hormone signaling and insulin-like growth factor-1 are strongly associated with protection from cancer and diabetes in both mice and humans; however, their role in cardiac function and cardiovascular diseases is controversial. Here, we review the link between growth factors, cardiac function, and heart disease with focus on the cardioprotective and sensitizing effect of growth factors in both model organisms and humans.

Lee et al. 2012

Starvation, detoxification and multi drug resistance in cancer therapy

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573885/

The selection of chemotherapy drugs is based on the cytotoxicity to specific tumor cell types and the relatively low toxicity to normal cells and tissues. However, the toxicity to normal cells poses a major clinical challenge, particularly when malignant cells have acquired resistance to chemotherapy. This drug resistance of cancer cells results from multiple factors including individual variation, genetic heterogeneity within a tumor, and cellular evolution. Much progress in the understanding of tumor cell resistance has been made in the past 35 years, owing to milestone discoveries such as the identification and characterization of ABC transporters. Nonetheless, the complexity of the genetic and epigenetic rewiring of cancer cells makes drug resistance an equally complex phenomenon that is difficult to overcome. In this review, we discuss how the remarkable changes in the levels of glucose, IGF-I, IGFBP-1 and in other proteins caused by fasting have the potential to improve the efficacy of chemotherapy against tumors by protecting normal cells and tissues and possibly by diminishing multidrug resistance in malignant cells.

Lee et al. 2012

Fasting Cycles Retard Growth of Tumors and Sensitize a Range of Cancer Cell Types to Chemotherapy . Sci Transl Med. 2012 Mar 7; 4(124): 124ra27.

Short-term starvation (or fasting) protects normal cells, mice, and potentially humans from the harmful side effects of a variety of chemotherapy drugs. Here we show that treatment with starvation conditions sensitized yeast cells (S. cerevisiae) expressing the oncogene-like RAS2val19 to oxidative stress and 15 of 17 mammalian cancer cell lines to chemotherapeutic agents. Cycles of starvation were as effective as chemotherapeutic agents in delaying progression of specific tumors and increased the effectiveness of these drugs against melanoma, glioma, and breast cancer cells. In mouse models of neuroblastoma, fasting cycles plus chemotherapy drugs— but not either treatment alone—resulted in long-term cancer-free survival. In 4T1 breast cancer cells, short- term starvation resulted in increased phosphorylation of the stress-sensitizing AKT and S6 kinases, increased oxidative stress, caspase-3 cleavage, DNA damage and apoptosis. These studies suggest that multiple cycles of fasting promote differential stress sensitization in a wide range of tumors and could potentially replace or augment the efficacy of certain toxic chemotherapy drugs in the treatment of various cancers.

Lee & Longo 2012

Oncogene (2011) 30, 3305–3316

The dietary recommendation for cancer patients receiving chemotherapy, as described by the American Cancer Society, is to increase calorie and protein intake. Yet, in simple organisms, mice, and humans, fasting—no calorie intake—induces a wide range of changes associated with cellular protection, which would be difficult to achieve even with a cocktail of potent drugs. In mammals, the protective effect of fasting is mediated, in part, by an over 50% reduction in glucose and insulin-like growth factor 1 (IGF-I) levels. Because proto-oncogenes function as key negative regulators of the protective changes induced by fasting, cells expressing oncogenes, and therefore the great majority of cancer cells, should not respond to the protective signals generated by fasting, promoting the differential protection (differential stress resistance) of normal and cancer cells. Preliminary reports indicate that fasting for up to 5 days followed by a normal diet, may also protect patients against chemotherapy without causing chronic weight loss. By contrast, the long-term 20 to 40% restriction in calorie intake (dietary restriction, DR), whose effects on cancer progression have been studied extensively for decades, requires weeks–months to be effective, causes much more modest changes in glucose and/or IGF-I levels, and promotes chronic weight loss in both rodents and humans. In this study, we review the basic as well as clinical studies on fasting, cellular protection and chemotherapy resistance, and compare them to those on DR and cancer treatment. Although additional pre-clinical and clinical studies are necessary, fasting has the potential to be translated into effective clinical interventions for the protection of patients and the improvement of therapeutic index.

Guevara- Aguirre et al. 2011

Sci Transl Med 3, 70ra13 (2011)

Clues to a Cancer- and Diabetes-Free Life

In the 1958 film Live Fast and Die Young, two reckless sisters threaten to burn out early. Similarly, one theory of aging predicts that a faster metabolism leads to a shorter life. Does this trade-off also apply to age-related disease? A new study by Guevara-Aguirre et al. offers clues that address this seminal question. The authors’ findings stem from studies of a unique group of Ecuadorian people who have a mutation in the growth hormone receptor (GHR) gene and a resulting insulin-like growth factor −1 (IGF-1) deficiency, which stunts their growth. These descendants of Spanish conversos, Jews who converted to Christianity to avoid the Inquisition, almost never get diabetes or cancer as a result, the authors postulate, of the privileged metabolic status that arises from their altered hormonal state. Relative to controls, these subjects show lower insulin concentrations and higher insulin sensitivity, and when stressed, their cells tend to self-destruct rather than accumulate mutations and DNA damage−−all features that are known to promote cell protection in model organisms.

For 22 years, this group of 99 related Ecuadorians−−most of whom are homozygous for an A-to-G splice site mutation at position 180 in exon 6 of the GHR gene−−has been monitored extensively, so that their health details are well documented. From this reservoir of data, plus information about the diseases of family members as well as causes of death of those relatives who have died, the authors deciphered that the Ecuadorian subjects who carried the GHR mutation had an abnormally low incidence of cancer and diabetes. The group showed only one case of nonlethal cancer and no cases of diabetes, whereas the controls −−unaffected relatives−−developed cancer (17%) and diabetes (5%) at rates similar to those of the Ecuadorian population as a whole.

To illuminate the underlying reason for the subjects’ freedom from these diseases, the authors focused on the components carried in their blood. In experiments on cultured human epithelial cells, Guevara-Aguirre et al. found that low concentrations of one of these, IGF-1, was responsible for preventing oxidative DNA damage when the cells were exposed to the oxidizing agent H2O2 and for promoting cell death when stress-related DNA damage did occur, a checkpoint that averts cancer-promoting behavior by abnormal cells. Analysis of the participating cell signaling pathways identified activation of the transcription factor FoxO under conditions of low IGF-1 as a likely mediator of these effects. Further, the lower blood insulin concentrations and higher insulin sensitivity in these subjects likely account for the absence of diabetes in this population.

Although it is difficult to prove that alterations in IGF-1 amounts are responsible for the cancer- and diabetes-free lives of these Ecuadorian people, genetic work from several model organisms suggests that this is so. In yeast, mutations in genes that encode components of a growth-promoting pathway protect against age-dependent genomic instability, and mutations in the insulin/IGF-1−like signaling pathway increase life span and reduce abnormal cellular proliferation in worms. Mice with defects in GH and IGF-1 live exceptionally long lives, with delayed appearance of age-dependent mutations and cancer. The Ecuadorians do not live longer-than-normal lives compared with their compatriots, but rather die in due course from causes of death other than cancer and diabetes complications. Thus, the metabolic inverse of ”live fast and die young”−−a slowed metabolism yields a longer life−−is not supported by the current findings. But a life free from two dreaded diseases may be considered a desirable trade-off.

Raffaghello et al. 2010

Fasting and differential chemotherapy protection in patients

Cell Cycle 9:22, 4474-4476

Chronic calorie restriction has been known for decades to prevent or retard cancer growth, but its weight-loss

effect and the potential problems associ- ated with combining it with chemother- apy have prevented its clinical application. Based on the discovery in model organ- isms that short term starvation (STS or fasting) causes a rapid switch of cells to a protected mode, we described a fasting- based intervention that causes remarkable changes in the levels of glucose, IGF-I and many other proteins and molecules and is capable of protecting mammalian cells and mice from various toxins, including chemotherapy. Because oncogenes prevent the cellular switch to this stress resistance mode, starvation for 48 hours or longer protects normal yeast and mammalian cells and mice but not cancer cells from chemotherapy, an effect we termed Differential Stress Resistance (DSR). In a recent article, 10 patients who fasted in combination with chemotherapy, reported that fasting was not only feasible and safe but caused a reduction in a wide range of side effects accompanied by an apparently normal and possibly augmented chemotherapy efficacy. Together with the remarkable results observed in animals, these data provide preliminary evidence in support of the human application of this fundamental biogerontology  finding, particularly for terminal patients receiving chemotherapy. Here we briefly discuss the basic, pre-clinical and clinical studies on fasting and cancer therapy.

Fontana et al. 2010

Extending Healthy Life Span—From Yeast to Humans

http://www.sciencemag.org/cgi/content/full/328/ 5976/321.

When the food intake of organisms such as yeast and rodents is reduced (dietary restriction), they live longer than organisms fed a normal diet. A similar effect is seen when the activity of nutrient- sensing pathways is reduced by mutations or chemical inhibitors. In rodents, both dietary restriction and decreased nutrient-sensing pathway activity can lower the incidence of age-related loss of function and disease, including tumors and neurodegeneration. Dietary restriction also increases life span and protects against diabetes, cancer, and cardiovascular disease in rhesus monkeys, and in humans it causes changes that protect against these age-related pathologies. Tumors and diabetes are also uncommon in humans with mutations in the growth hormone receptor, and natural genetic variants in nutrient-sensing pathways are associated with increased human life span. Dietary restriction and reduced activity of nutrient-sensing pathways may thus slow aging by similar mechanisms, which have been conserved during evolution. We discuss these findings and their potential application to prevention of age-related disease and promotion of healthy aging in humans, and the challenge of possible negative side effects.

Lee et al. 2010

Cancer Res; 70(4); 1564–72

Reduced Levels of IGF-I Mediate Differential Protection of Normal and Cancer Cells in Response to Fasting and Improve Chemotherapeutic Index

Inhibitors of the insulin-like growth factor-I (IGF-I) receptor have been widely studied for their ability to enhance the killing of a variety of malignant cells, but whether IGF-I signaling differentially protects the host and cancer cells against chemotherapy is unknown. Starvation can protect mice, but not cancer cells, against high-dose chemotherapy [differential stress resistance (DSR)]. Here, we offer evidence that IGF-I reduction mediates part of the starvation-dependent DSR. A 72-hour fast in mice reduced circulating IGF-I by 70% and increased the level of the IGF-I inhibitor IGFBP-1 by 11-fold. LID mice, with a 70% to 80% reduction in circulating IGF-I levels, were protected against three of four chemotherapy drugs tested. Restoration of IGF-I was sufficient to reverse the protective effect of fasting. Sixty percent of melanoma-bearing LID mice treated with doxorubicin achieved long-term survival whereas all control mice died of either metastases or chemotherapy toxicity. Reduc- ing IGF-I/IGF-I signaling protected primary glia, but not glioma cells, against cyclophosphamide and protected mouse embryonic fibroblasts against doxorubicin. Further, S. cerevisiae lacking homologs of IGF-I signaling pro- teins were protected against chemotherapy-dependent DNA damage in a manner that could be reversed by ex- pressing a constitutively active form of Ras. We conclude that normal cells and mice can be protected against chemotherapy-dependent damage by reducing circulating IGF-I levels and by a mechanism that involves down- regulation of proto-oncogene signals

Longo & Fontana 2010

Trends Pharmacol Sci. 2010 February ; 31(2): 89–98Calorie restriction and cancer prevention: metabolic and molecular mechanisms

An important discovery of recent years has been that lifestyle and environmental factors affect cancer initiation, promotion and progression, suggesting that many malignancies are preventable. Epidemiological studies strongly suggest that excessive adiposity, decreased physical activity, and unhealthy diets are key players in the pathogenesis and prognosis of many common cancers. In addition, calorie restriction (CR), without malnutrition, has been shown to be broadly effective in cancer-prevention in laboratory strains of rodents. Adult-onset moderate CR also reduces cancer incidence by 50% in monkeys. Whether the anti-tumorigenic effects of CR will apply to humans is unknown, but CR results in a consistent reduction in circulating levels of growth factors, anabolic hormones, inflammatory cytokines and oxidative stress markers associated with various malignancies. Here, we discuss the link between nutritional interventions and cancer prevention with focus on the mechanisms that may be responsible for these effects in simple systems and mammals with a view to developing chemoprevention agents.

Sadie et al. 2009

Fasting and Cancer Treatment in Humans: A Case series report

AGING, December 2009 Vol.1 No 12 1-18

Abstract: Short‐term fasting (48 hours) was shown to be effective in protecting normal cells and mice but not cancer cells against high dose chemotherapy, termed Differential Stress Resistance (DSR), but the feasibility and effect of fasting in cancer patients undergoing chemotherapy is unknown. Here we describe 10 cases in which patients diagnosed with a variety of malignancies had voluntarily fasted prior to (48‐140 hours) and/or following (5‐56 hours) chemotherapy. None of these patients, who received an average of 4 cycles of various chemotherapy drugs in combination with fasting, reported significant side effects caused by the fasting itself other than hunger and lightheadedness. Chemotherapy associated toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (NCI). The six patients who underwent chemotherapy with or without fasting reported a reduction in fatigue, weakness, and gastrointestinal side effects while fasting. In those patients whose cancer progression could be assessed, fasting did not prevent the chemotherapy‐induced reduction of tumor volume or tumor markers. Although the 10 cases presented here suggest that fasting in combination with chemotherapy is feasible, safe, and has the potential to ameliorate side effects caused by chemotherapies, they are not meant to establish practice guidelines for patients undergoing chemotherapy. Only controlled‐randomized clinical trials will determine the effect of fasting on clinical outcomes including quality of life and therapeutic index.

Jennifer Couzin – News of the Week

Can Fasting Blunt Chemotherapy’s Debilitating Side Effects?

SCIENCE VOL 321 1146-7

Raffaghello et al. 2008

Starvation-dependent differential stress resistance protects normal but not cancer cells against

high-dose chemotherapy

http://www.pnas.org cgi doi 10.1073 pnas.0708100105

Strategies to treat cancer have focused primarily on the killing of tumor cells. Here, we describe a differential stress resistance (DSR) method that focuses instead on protecting the organism but not cancer cells against chemotherapy. Short-term starved S. cerevisiae or cells lacking proto-oncogene homologs were up to 1,000 times better protected against oxidative stress or chemotherapy drugs than cells expressing the oncogene homolog Ras2val19. Low- glucose or low-serum media also protected primary glial cells but not six different rat and human glioma and neuroblastoma cancer cell lines against hydrogen peroxide or the chemotherapy drug/ pro-oxidant cyclophosphamide. Finally, short-term starvation pro- vided complete protection to mice but not to injected neuroblas- toma cells against a high dose of the chemotherapy drug/pro- oxidant etoposide. These studies describe a starvation-based DSR strategy to enhance the efficacy of chemotherapy and suggest that specific agents among those that promote oxidative stress and DNA damage have the potential to maximize the differential toxicity to normal and cancer cells.

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