Toxicity in Chemotherapy — When Less Is More

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Alessandro Laviano and Filippo Rossi Fanelli. N Engl J Med 2012; 366:2319-2320 June 14, 2012

Food is a potent inducer of metabolic responses. Specific nutrients enhance muscle accretion, while others modulate the inflammatory response or boost appetite. On the other hand, caloric restriction under normal conditions (i.e., the prolonged intake of approximately 20 to 40% fewer calories than are required) has been shown to protect against the development of chronic diseases.1 Exploiting the differential effects of food and its absence on metabolic pathways during disease may be one strategy to enhance the efficacy of drug therapies.
Significant improvements in the field of oncology have enhanced prevention, screening, early diagnosis, and treatment. Nevertheless, the prevalence of cancer remains high, the costs of treatment are great, and cures for most cancers have yet to be found. The possibility that a patient’s response to anticancer therapy might be improved through changes in diet is attractive, since this approach is likely to be affordable and readily accessible.
Normal cells and cancer cells differ in their ability to respond to fasting. In the absence of nutrients, normal cells switch their metabolism toward maintenance pathways, whereas tumor cells are unable to activate this protective response. The differences in metabolism between normal cells and cancer cells could be used to enhance anticancer therapy by selectively increasing the resistance of normal cells to chemotherapy — that is, by augmenting differential stress resistance rather than by developing more aggressive and toxic drugs

Figure 1. Modulating the Effects of Chemotherapy by Means of Fasting.
Chemotherapy-induced oxidative stress reduces the rates of both the proliferation and the survival of cancer cells. It yields an objective response that can be quantified on the basis of shrinkage of the tumor volume (Panel A). However, chemotherapy also affects normal cells, leading to toxic side effects. Lee et al.2 recently reported that short-term fasting before or after chemotherapy, or at both times, induces differential stress resistance in normal and cancer cells. In normal cells, fasting activates protective metabolic pathways that confer resistance to oxidative stress (Panel B). In contrast, yeast transformed with an activated oncogene is unable to turn on the protective response and thus remains sensitive to oxidative stress. Additional experiments using mouse models of human cancer showed that fasting specifically augments levels of oxidative stress and sensitivity to oxidative damage (e.g., that inflicted by chemotherapeutic agents) in cancer cells and that these effects are accompanied by DNA damage and apoptosis

Lee et al.2 recently described data that support this approach. They found that short-term starvation increased the sensitivity of yeast cells that expressed an activated form of oncogene to oxidative stress, and thus to chemotherapy, as compared with its effect on wild-type yeast cells. Also, they found that restricting glucose and growth factors in the culture medium for 24 hours before and 24 hours after treatment with doxorubicin and cyclophosphamide rendered 15 of 17 cell lines more sensitive to these drugs.

To confirm these effects in vivo, Lee et al. studied mice with subcutaneous allografts of murine cancers or xenografts of human cancer cells. They observed that 48 to 60 hours of food deprivation retards tumor growth, in some cases as effectively as chemotherapy does, and they noted a synergy between starvation and drug therapy. Then, to investigate the effects of short-term starvation on metastatic advanced cancer, they studied mice bearing melanoma, neuroblastoma, or breast-cancer cells and observed that fasting potentiated the effects of chemotherapy and extended survival in these animals. They investigated the molecular mechanisms underlying these biologic effects, although only in breast-cancer allografts. After fasting, proliferation-associated genes were down-regulated in normal tissues but were up-regulated or unaffected in cancer cells. In addition, levels of phosphorylated Akt and S6K were elevated in the cancer cells of animals that had fasted, suggesting that levels of oxidative stress and sensitization to oxidative damage (a primary effect of chemotherapy in these cancer cells) were increased.

It is tempting to integrate these exciting results into the current comprehensive approach to patients with cancer.3 But this action would be premature. During the period of refeeding after fasting, several of the experimental cancers observed by Lee et al. returned to a size similar to those in control animals. The use of caloric restriction, as opposed to short-term starvation, is not advised in patients with cancer who are already prone to malnutrition owing to the tumor or to the side effects of anticancer therapies. Studies in animals suggest that it could take months of caloric restriction to bring about an antitumor response in humans, if at all. Malnutrition would inevitably develop, leading to increased morbidity and mortality.

Clinical trials could be considered as a way of testing the effects of fasting or of restricting specific nutrients for 2 or 3 days during and after chemotherapy. With respect to palliative care, preliminary results suggest that the integration of differential stress resistance may enhance patients’ responsiveness to and compliance with anticancer therapies. In a case series of 10 patients with cancer who voluntarily underwent short-term fasting prior to or after chemotherapy (or at both times), fatigue, weakness, and gastrointestinal side effects were reduced.4 Clinical trials are currently under way to test the effect of short-term fasting on chemotherapy-associated toxicity ( numbers, NCT01304251, NCT00936364, and NCT01175837). Although strong evidence has yet to be obtained to support the use of differential stress resistance as achieved through fasting for improving the response to chemotherapy, it may not be long in coming.5

1. Fontana L, Partridge L, Longo VD. Extending healthy life span — from yeast to humans. Science 2010;328:321-326
2. Lee C, Raffaghello L, Brandhorst S, et al. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med 2012;4:124ra27-124ra27
3. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 2010;363:733-742
4. Safdie FM, Dorff T, Quinn D, et al. Fasting and cancer treatment in humans: a case series report. Aging (Albany NY) 2009;1:988-1007
5. Laviano A, Seelaender M, Sanchez-Lara K, Gioulbasanis I, Molfino A, Rossi Fanelli F. Beyond anorexia-cachexia: nutrition and modulation of cancer patients’ metabolism: supplementary, complementary or alternative anti-neoplastic therapy? Eur J Pharmacol 2011;668:Suppl:S87-S90

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