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Medicine » Oncology » "Topics in Cancer Survivorship", book edited by Ravinder Mohan, ISBN 978-953-307-894-6, Published: January 27, 2012 under CC BY 3.0 license. © The Author(s).

Chapter 10

Nutritional Supplements for Cancer-Associated

By Garth L. Nicolson
DOI: 10.5772/23713

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Nutritional Supplements for Cancer-Associated Fatigue and Cancer Therapy – A Molecular Basis for Restoring Mitochondrial Function

Garth Nicolson 1

1. Introduction

Cancer patients routinely take multiple – dietary supplements to prevent recurrence or chronic disease, to improve quality of life and overall health, or to reduce the adverse effects of cancer therapy (Gansler et al., 2008; Miller et al., 2009; Ströhle et al., 2010; Velicer & Ulrich, 2008). In fact, one of the most common behavior changes among cancer patients is the use of dietary supplements (Miller et al., 2009).

Although cancer patients routinely use dietary supplements, there is often little consideration as to their safety, efficacy and potential negative effects (Cassileth et al., 2009; Giovannucci & Chan, 2010). In fact, some data suggest that higher than recommended doses of some vitamins and minerals might result in enhancement of carcinogenesis, changes in survival in some cancers and interference with therapy or prescription medications (Cassileth et al., 2009; Giovannucci & Chan, 2010). Nonetheless, several potentially beneficial effects of dietary supplements have been recorded, including reductions in the risk of cancer carcinogenesis and tumor progression, enhancement of immune responses against cancers or immune systems in general, improvements in nutrition and general health, and reductions in the adverse effects of cancer therapy (Cassileth et al., 2009; Doyle et al., 2006; Isenring et all, 2010; Miller et al., 2009; Conklin, 2000; Nicolson & Conklin, 2008; Nicolson, 2010; Ströhle et al., 2010),

This review will concentrate on one particularly troublesome aspect of cancer and cancer therapy—cancer-associated fatigue.

2. The importance of cancer-associated fatigue

Cancer-associated fatigue adds considerably to cancer morbidity (Brown & Kroenke, 2009; Hofman et al., 2007). It exists in all types of cancers from the least to the most progressed cancers (Brown & Kroenke, 2009; Hofman et al., 2007). Along with pain and nausea, it is one of the most common and troublesome symptoms of cancer (Hofman et al., 2007; Prue et al., 2006), especially in advanced cancers (Curt et al., 2000; Prue et al., 2006; Respini et al., 2003).

In patients receiving adjuvant therapies the prevalence of cancer-associated fatigue is reported to be as high as 95% (Sood & Moynihan, 2005). Thus cancer-associated fatigue is a problem before, during and after therapy and can continue to be a problem years after cancer treatment (Curt et al., 2000; Hofman et al., 2007). Cancer-associated fatigue has a very strong negative effect on quality of life; therefore, addressing and reducing cancer-associated fatigue should be an important consideration in the treatment of cancer (Curt et al., 2000; Nicolson, 2010).

Although not well understood, cancer-associated fatigue is thought to be a combination of the effects of having cancer plus the effects of cancer treatments (Curt et al., 2000; Hofman et al., 2007). Unfortunately, cancer-associated fatigue is rarely treated, and is often thought to be an unavoidable symptom (Brown & Kroenke, 2009; Hofman et al., 2007).

Cancer-associated fatigue can be considered to be the product of a variety of contributing factors (Ahlberg et al., 2003). In addition to a decrease in the availability of cellular energy, there are psychological factors, such as the presence of depression, anxiety, sleep disturbances, among others, as well as anemia, endocrine changes, poor nutritional status, release of inflammatory cytokines and cancer therapy that can all contribute to cancer-associated fatigue (Ahlberg et al., 2003; Gutstein, 2001; Manzullo & Escalante, 2002; Sood & Moynihan, 2005). Thus cancer-associated fatigue does not occur as an isolated symptom; rather, it occurs as one of multiple symptoms that are present in cancer patients. Similar to some other symptoms in cancer patients, the severity of cancer-associated fatigue correlates with decreased functional abilities (Given et al., 2001).

Cancer therapy also contributes to cancer-associated fatigue (Sood & Moynihan, 2005). In fact, the most commonly found and disabling effect of cancer therapy is fatigue (Given et al., 2001; Sood & Moynihan, 2005; Vogelzang et al., 1997). During cancer therapy fatigue problems can vary, from mild to severe, and excess fatigue during cancer therapy is a significant reason why patients discontinue therapy (Liu et al., 2005). Reviewing articles on the effects of cancer therapy on fatigue, it was noted that 80-96% of patients receiving chemotherapy and 60-93% receiving radiotherapy experienced moderate to severe fatigue, and fatigue continued for months to years after cancer therapy ended (Manzullo & Escalante, 2002). Therefore, in cancer patients controlling cancer-associated fatigue as well as therapy-induced fatigue are both important strategies (Marrow, 2007).

There have been efforts at understanding and treating cancer-associated fatigue as well as developing ways to distinguish between depression and cancer-associated fatigue (Brown & Kroenke, 2009). Both cancer-associated fatigue and depression have multidimensional and heterogeneous qualities, possessing physical, cognitive and emotional dimensions and a certain degree of overlap across these dimensions (Brown & Kroenke, 2009; Sood & Moynihan, 2005). In cancer patients fatigue or loss of energy is a core aspect of diagnosing depression—thus both fatigue and depression are often diagnosed together. This is usually accomplished by self-assessment, where fatigue and depression are considered to be part of a clinical symptom cluster, co-morbitity or syndrome (Arnold, 2008; Bender et al., 2008). There are techniques, moreover, that can distinguish between these two different symptoms by removal of fatigue-associated assessments from an analysis of depression (Smets et al., 1996; Stone et al., 2000). When assessing fatigue or cancer-associated fatigue, criteria have been established that take depression into consideration, and these two symptoms can thus be separated out by considering unshared properties (Cella et al., 2001).

Chronic or intractable fatigue lasting more than 6 months that is not reversed by normal sleep is the most common complaint of patients seeking general medical care (Kroenke et al., 1988; Morrison, 1980). It occurs naturally during aging and is also an important secondary condition in many clinical diagnoses (Kroenke et al., 1988; McDonald et al., 1993). Most fatigued patients understand fatigue as a loss of energy and inability to perform even simple tasks without exertion. Many medical conditions are associated with fatigue, including respiratory, coronary, musculoskeletal, and bowel conditions as well as infections (Kroenke et al., 1988; McDonald et al., 1993; Morrison, 1980). However, this symptom is especially important in the overwhelming majority of cancer patients (Ahlberg et al., 2003; Curt et al., 2000; Hofman et al., 2007; Sood, & Moynihan, 2005).

3. Oxidative stress and damage to mitochondrial membranes – Relationship to fatigue

Another phenomenon associated with cancer and its progression as well as aging and age-related degenerative diseases is oxidative stress (Dreher & Junod,1996; Halliwell, 1996; Kehrer, 1993). Oxidative stress is caused by an intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over intracellular antioxidants. When this imbalance occurs, it results in oxidation of cellular structures, such as membrane lipids and proteins, and mutation of mitochondrial and nuclear DNA (Abidi & Ali, 1999; Bartsch & Nair, 2004; Marnett, 2000; Stadtman, 2002). ROS and RNS are naturally occurring cellular free radical oxidants that are usually present in low concentrations and are involved in gene expression, intracellular signaling, cell proliferation, antimicrobial defense and other normal cellular processes (Castro & Freeman, 2001; Ghaffari, 2008; Johnson et al., 1996). However, when ROS/RNS are in excess over cellular antioxidants, damage can occur to cellular structures (Abidi & Ali, 1999; Castro & Freeman, 2001; Ghaffari, 2008; Maes & Twisk, 2009). Recently Maes (2009) has proposed a link between excess oxidative stress (and activation of ROS/RNS pathways and fatigue and fatiguing illnesses.

Under normal physiological conditions our cellular antioxidant defenses usually maintain ROS/RNS at appropriate concentrations that prevent excess oxidation of cellular structures (Barber & Harris, 1994; Fridovich,1995; Sun, 1990). Endogenous cellular antioxidant defenses include glutathione peroxidase, catalase and superoxide dismutase, among other enzymes (Jagetia et al., 2003; Seifried et al., 2003), and low molecular weight dietary antioxidants (Aeschbach et al., 1994; Schwartz,1996). Some of these dietary antioxidants have been used as natural chemopreventive agents to shift the excess concentrations of oxidative molecules towards more physiological levels (Prasad et al., 2001; Tanaka, 1994).

Excess oxidative stress (or primarily its mediators—excess ROS/RNS) within cancer cells has been linked to promotion and progression of malignancy of cancers (Brown & Bicknell, 2001; Klaunig & Kamendulis, 2004; Ray et al., 2000; Tas et al., 2005; Toyokuni et al., 1995). Thus oxidative stress and antioxidant status have been examined in various malignant cancers, such as breast (Brown & Bicknell, 2001; Kang, 2002; Ray et al., 2000; Tas et al., 2005), prostate (Aydin et al., 2006; Sikka, 2003), colorectal (Otamiri & Sjodahl,1989; Oxdemirler et al., 1989), renal (Asal et al., 1990; Gago-Dominguez et al., 2002), and other malignancies (Batcioglu et al., 2006; Manoharan et al., 2005; Seril et al., 2003). In all of these cancers ROS/RNS were in excess of antioxidant concentrations, resulting in cellular oxidative stress. Thus these cancers could possibly have been induced as a consequence of excess ROS/RNS and oxidative damage to the genetic apparatus (Abidi & Ali, 1999; Dreher & Junod, 1996; Jaruga et al., 1992). Even more likely than carcinogenesis is the promotion of progression of tumors that might not evolve to malignancy in the absence of excess oxidative stress (Nicolson, 2010; Nicolson & Conklin, 2008).

4. Cancer therapy causes excess oxidative stress and severe fatigue

The most common therapies used against cancers, such as chemotherapy, can result in the generation of excess ROS/RNS (Conklin, 2000; 2004). Thus cancer therapy and the resulting production of excess oxidative stress can damage biological systems other than tumors (Conklin, 2004; Nicolson, 2010; Nicolson & Conklin, 2008). During chemotherapy the highest known levels of oxidative stress are generated by anthracycline antibiotics, followed (in no particular order) by alkylating agents, platinum-coordination complexes, epipodophyllotoxins, and camptothecins (Conklin, 2004). The primary site of ROS/RNS generation during cancer chemotherapy is the cytochrome P450 monooxygenase system within liver microsomes. Enzyme systems such as the xanthine-xanthine oxidase system, and non-enzymatic mechanisms (Fenton and Haber-Weiss reactions) also play a role in creating excess oxidative stress during chemotherapy. The very high levels of oxidative stress caused by anthracyclines are also related to their ability to displace coenzyme Q10 (CoQ10) from the electron transport system of cardiac mitochondria, resulting in diversion of electrons directly to molecular oxygen with the formation of superoxide radicals (Conklin, 2000; 2004).

Although anthracyclines and other chemotherapeutic agents cause generation of high levels of ROS/RNS, not all chemotherapeutic agents generate excess oxidative stress. Some agents generate only modest amounts of ROS/RNS. Examples of this are: platinum-coordination complexes and camptothecins, taxanes, vinca alkaloids, anti-metabolites, such as the antifolates, and nucleoside and nucleotide analogues (Conklin, 2000; 2004; Nicolson & Conklin, 2008). Most chemotherapeutic agents do, however, generate some oxidative stress, as do all anti-neoplastic agents when they induce apoptosis in cancer cells. Drug-induced apoptosis is usually triggered by the release of cytochrome c from the mitochondrial electron transport chain. When this occurs, electrons are diverted from NADH dehydrogenase and reduced CoQ10 to oxygen, resulting in the formation of superoxide radicals (Betteridge, 2000; Conklin, 2000).

Use of chemotherapeutic agents to treat cancer causes oxidative stress that produces side effects, including fatigue. This can reduce the efficacy of therapy (Nicolson & Conklin, 2008; Nicolson, 2010). Many anti-neoplastic agents have clearly established mechanisms of action that are not dependent upon the generation of ROS/RNS; however, these drugs can only mediate their anticancer effects on cancer cells that exhibit unrestricted progression through the cell cycle and have intact apoptotic pathways. Oxidative stress interferes with cell cycle progression by inhibiting the transition of cells from the G0 to G1 phase, slowing progression through S phase by inhibition of DNA synthesis, inhibiting cell cycle progression of G1 to S phase, and by checkpoint arrest (Balin et al., 1978; Gonzalez, 1992; Hauptlorenz et al., 1985; Kurata, 2000; Schackelford et al., 2000).

Chemotherapeutic agents can also activate DNA repair systems. DNA repair of damage caused by alkylating agents and platinum complexes results in resistance to these drugs, and checkpoint arrest during oxidative stress can enhance the repair processes and diminish the efficacy of treatment (Fojo, 2001; Wei et al., 2000; Zhen et al., 1992). Abolishing checkpoint arrest produces the opposite effect and enhances the cytotoxicity of antineoplastic agents. By reducing oxidative stress, antioxidants counteract the effects of chemotherapy-induced oxidative stress on the cell cycle and enhance the cytotoxicity of antineoplastic agents (Conklin, 2004).

Oxidative stress can affect important intracellular signal transduction pathways that are necessary for the action of some antineoplastic agents (Conklin, 2004; Hampton et al., 1998; Shacter et al., 2000). There are two major pathways of drug-induced apoptosis following cellular damage by antineoplastic agents: the mitochondrial pathway, initiated by release of cytochrome c, and the CD95 death receptor pathway, initiated by CD95L binding to its death receptor (Fojo, 2001). Oxidative stress during chemotherapy results in the generation of highly electrophilic aldehydes that have the ability to bind to the nucleophilic active sites of caspases as well as the extracellular domain of the CD95 death receptor. This inhibits caspase activity and the binding of CD96L ligand, and this results in the impairment of the ability of antineoplastic agents to initiate apoptosis (Chandra et al., 2000; Hampton et al., 1998; Shacter et al., 2000).

In addition to chemotherapy, radiotherapy also results in generation of oxidative stress and excess ROS/RNS (Feinendegen et al., 2007; Greenberger et al., 2001). The principal target of radiation is tumor cell DNA, and this can be directly damaged by radiation. However, genetic damage is also mediated by excess ROS/RNS (Epperly et al., 2003; Feinendegen et al., 2007). Recently the principal source of excess ROS/RNS during radiotherapy has been shown to be the mitochondria (Epperly et al., 2003; Sabbarova & Kanai, 2007). The initial cytotoxicity of radiation is now thought to be due to excess ROS/RNS triggering of apoptosis via alteration of mitochondrial metabolism. This causes transiently opening of mitochondrial permeability transition pores, which increases the influx of calcium ions into the matrix. The influx of calcium ions stimulates mitochondrial nitric oxide synthase and generation of nitric oxide, which inhibits the respiratory chain and eventually stimulates excess ROS/RNS free radicals that initiate apoptosis (Leach et al., 2002; Sabbarova & Kanai, 2007).

5. Cancer therapy and mitochondrial damage

Cancer therapy is associated with several adverse side effects. One of the most difficult side effects is caused by chemotherapeutic drug damage to mitochondria (Conklin, 2000; Nicolson & Conklin, 2008). Cardiac mitochondria are especially sensitive to certain chemotherapy agents, such as anthracycline antibiotics (Conklin, 2004). Anthracycline-induced cardiac toxicity is characterized by acute, reversible toxicity that causes electrocardiographic changes and depressed myocardial contractility and by chronic, irreversible, dose-related cardiomyopathy (Conklin, 2004; 2005). The selective anthracycline-induced toxicity to cardiac cells is due to damage of cardiac mitochondria. The sensitivity of cardiac cells to anthracyclines, such as doxorubicin, has been found to be due to the unique properties of cardiac mitochondria in that they possess a Complex I-associated NADH dehydrogenase in the inner mitochondrial membrane facing the cytosol (Lehninger, 1951; Rasumssen & Rasmussen, 1985).

Doxorubicin is a relatively small molecule, and because of this property it readily penetrates the outer mitochondrial membrane. However, because it is hydrophilic and cannot partition into the lipid membrane matrix, it cannot penetrate the inner mitochondrial membrane (Conklin, 2005; Nohl, 1987). Thus, it cannot participate in oxidation-reduction reactions with the type of inner matrix-facing, electron transport chain dehydrogenases found in most types of cells, including most tumor cells (Conklin, 2005; Nohl, 1987). But in heart cells doxorubicin can interact with the mitochondrial cytosolic-facing NADH dehydrogenase that is unique to this tissue (Davies & Doroshow, 1986; Doroshow & Davies, 1986). This interaction produces doxorubicin aglycones, which are highly lipid soluble and readily penetrate the inner mitochondrial membrane (Conklin, 2005; Gille & Nohl, 1997). At this location they can displace CoQ10 from the electron transport chain (Conklin, 2005; Davies & Doroshow, 1986).

The displacement of CoQ10 from the electron transport chain during doxorubicin treatment results in decreases of CoQ10 in cardiac muscle (Karlsson et al., 1986) as the plasma concentration of CoQ10 increases (Eaton et al., 2000). CoQ10 normally accepts electrons from Complexes I and II and transfers them down the electron transport chain, resulting in the formation of water. However, the presence of aglycones in the inner mitochondrial membrane and inner matrix results in the transfer the electrons directly to molecular oxygen, resulting in the formation of superoxide radicals (Papadopoulou & Tsiftsoglou, 1996). Thus, doxorubicin generates a high level of oxidative stress in cardiac mitochondria, causing acute cardiac toxicity and damage to mitochondrial DNA (Conklin, 2005; Doroshow & Davies, 1986; Palmeira et al., 1991).

Anthracycline-damaged cardiac cell mitochondria cannot sustain their function, and changes in their structure results in disruption of mitochondria and eventually apoptosis (Serrano et al., 1999; Conklin, 2005; Gille & Nohl, 1997). This produces cardiac insufficiency and an inability to respond to pharmacological interventions, resulting ultimately in cardiac failure. However, if CoQ10 is administered during anthracycline chemotherapy, damage to the heart is prevented by decreasing anthracycline metabolism within cardiac mitochondria and by competing with aglycones for the CoQ10 sites within the electron transport chain (Conklin, 2005). Thus, CoQ10 administered concurrently with anthracyclines can maintain the integrity of cardiac mitochondria and prevent damage to the heart, and at the same time enhancing the anti-cancer activity of anthracyclines (Conklin, 2000; 2005).

In addition to chemotherapy, radiotherapy also produces damage to tissues other than cancerous tissues. Agents that protect tissues against radiation effects have been used to reduce unwanted damage (Brizel, 2007; Sabbarova & Kanai, 2007).

Radioprotective agents that have been used to decrease the adverse effects of radiotherapy are: antioxidants, free radical scavengers, inhibitors of nitric oxide synthase and anti-inflammatory and immunomodulatory agents (Brizel, 2007; Sabbarova & Kanai, 2007). The most effective of these under development target mitochondria, such as proteins and peptides that can be transported into mitochondria and plasmids or nucleotide sequences, for example, agents that target and stimulate mitochondrial manganese superoxide dismutase genes to produce this important dismutase have been used as radioprotective agents (Sabbarova & Kanai, 2007).

6. Molecular replacement of mitochondrial components during cancer therapy

As discussed in Section 5, chemotherapy can displace important mitochondrial cofactors, such as CoQ10 (Conklin, 2000; 2005). During chemotherapy replacement of CoQ10 dramatically prevents development of anthracycline-induced cardiomyopathy and histopathological changes. It can also prevent changes in electrocardiograms (EKG) characteristic of anthracycline-induced heart damage (Domae et al., 1981). Indeed, the administration of CoQ10 to animals resulted in increased survival, improvement in the EKG patterns, and reduced heart histopathological changes (Usui et al., 1982). These preclinical data, along with clinical data (discussed in Conklin, 2004 and Nicolson & Conklin, 2008) support the contention that CoQ10 protects the heart tssue from anthracycline-induced damage.

During chemotherapy of cancer, patients have received concurrent administration of CoQ10. This can affect both acute and chronic cardiotoxicity caused by anthracyclines (Conklin, 2004; 2005; Nicolson & Conklin, 2008). For example, Judy et al. (1984) studied the importance of administering CoQ10 on the development of doxorubicin-induced cardiotoxicity in patients with lung cancer. Doxorubicin given alone without CoQ10 caused marked impairment of cardiac function with a significant increase in heart rate and a substantial decrease in ejection fraction, stroke index and cardiac index. In contrast, doxorubicin administered along with CoQ10, did not cause cardiotoxicity—cardiac function remained unchanged. Other studies have confirmed these results and have shown that CoQ10 can reduce the cardiac toxicity of doxorubicin in adults (Buckingham et al., 1997; Cortes et al., 1978) and children (Iarussi et al., 1994; Loke et al., 2006).

Thus in preclinical and clinical studies the data indicate that CoQ10 protects the heart from the cardiotoxicity of anthracyclines. The impact of CoQ10 on the anti-neoplastic efficacy of anthracycline-based chemotherapy, however, was not studied in these reports (Buckingham et al., 1997; Cortes et al., 1978; Iarussi et al., 1994; Loke et al., 2006).

7. Cancer-associated fatigue and other cancer-associated conditions

The most common complaint of patients undergoing anti-neoplastic therapy is fatigue, but there are also other complaints that include: pain, nausea, vomiting, malaise, diarrhea, headaches, rashes and infections (Buckingham et al., 1997; Loke et al., 2006; Manzullo & Escalante, 2002). Other more serious problems can also occur, such as cardiomyopathy, peripheral neuropathy, hepatotoxicity, pulmonary fibrosis, mucositis and other effects (Buckingham et al., 1997; Liu et al., 2005; Loke et al., 2006; Manzullo & Escalante, 2002). Due to misconceptions among patients and their physicians, most patients feel that cancer therapy-associated fatigue is an untreatable symptom (Vogelzang et al., 1997). Although fatigue is usually the most commonly reported adverse symptom during cancer therapy, up until recently there was little effort directed at reducing fatigue before, during or after cancer therapy (Von Roenn & Paice, 2005). This has changed recently (Nicolson, 2010; Nicolson & Conklin, 2008).

Reducing cancer-associated fatigue and fatigue associated with cancer therapy are now considered important therapeutic goals. Psychological, physical, pharmaceutical and nutraceutical methods have been undertaken to reduce fatigue and improve the quality of life of cancer patients (Borneman et al., 2007; Escalante et al., 2011; Nicolson, 2010). These treatments are based on suppressing fatigue but also on controlling co-morbid or related symptoms, such as pain, anemia, cachexia, sleep disorders, depression and other symptoms (Escalante et al., 2011; Mustian et al., 2007; Nicolson, 2010; Ryan et al., 2007; Watson & Mock, 2004; Zee & Acoli-Isreal, 2009).

Unfortunately, there is no standard protocol related to treating cancer-associated fatigue and related symptoms. In reviewing the types of supportive measures used to control fatigue and related symptoms, the data suggest that graded exercise, nutritional support, treatment of psychological problems (such as depression with certain anti-depressants or psycostimulants), treatment of anemia with hematopoetic growth factors and control of insomnia with cognitive behavioral therapy or pharmacological and nonpharmacological therapies all have a role to various degrees in controlling cancer-associated fatigue (Escalante et al., 2011; Mustian et al., 2007; Nicolson, 2010; Ryan et al., 2007; Watson & Mock, 2004; Zee & Acoli-Isreal, 2009). Some of these approaches using pharmacological drugs and growth factors have been systematically analyzed in 27 studies (meta-analysis) by Milton et al. (2008). In this limited analysis, only a psycostimulant (methylphenidate) and hematopoetic growth factors (erythropoietin and darbopeitin) were more effective than placebo treatments. Other treatments were no better than placebo in the treatment of cancer-related fatigue (Milton et al., 2008).

8. Cancer-associated fatigue, aging and oxidative mitochondrial damage

Cancer-associated fatigue has been defined as a multidimensional sensation (McDonald et al., 1993; Milton et al., 2008; Mustian et al., 2007; Ryan et al., 2007). Most patients understand fatigue as a loss of energy and inability to perform even simple tasks without exertion (Levy, 2008; Milton et al., 2008). Cancer-associated fatigue has been described as the dysregulation of several interrelated physiological, biochemical and psychological systems (Mustian et al., 2007; Ryan et al., 2007), but at the tissue and cellular levels fatigue is related to reductions in the efficiency of cellular energy systems, mainly found in mitochondria (Agadjanyan et al., 2003; Nicolson, 2003; 2005). Damage to mitochondrial components, mainly by ROS/RNS oxidation, can impair mitochondrial function, and this can also result in oxidative damage (reviewed in Bartsch & Nair, 2004; Castro & Freeman, 2001; Kehrer, 1993). Mitochondrial membranes and DNA are major targets of oxidative stress, and with aging ROS/RNS mitochondrial damage can accumulate (Huang & Manton, 2004; Wei & Lee, 2002).

During aging and in certain medical conditions oxidative damage to mitochondrial membranes impairs mitochondrial function (Huang & Manton, 2004; Logan & Wong, 2001; Wei & Lee, 2002). For example, in chronic fatigue syndrome patients there is evidence of oxidative damage to DNA and lipids (Logan & Wong, 2001; Manuel y Keenoy et al., 2001) as well as oxidized blood markers (Richards et al., 2000) and muscle membrane lipids (Felle et al., 2000) that are indicative of excess oxidative stress (Dianzani, 1993). In chronic fatigue syndrome patients also have sustained elevated levels of peroxynitrite due to excess nitric oxide, which can result in lipid peroxidation and loss of mitochondrial function as well as changes in cytokine levels that exert a positive feedback on nitric oxide production, increasing the rate of membrane damage (Pall, 2000).

9. Molecular replacement of oxidized membrane components and its effect on fatigue

In cancer patients mitochondrial membranes as well as other cellular membranes are especially sensitive to oxidative damage by ROS/RNS, which occurs at high rates in cancer (Batcioglu et al., 2006; Dianzani, 1993; Gago-Dominguez et al., 2002; Manoharan et al., 2005; Otamiri & Sjodahl, 1989; Oxdemirler et al., 1989; Seril et al., 2003). Oxidation of membrane phospholipids alters their structure, affecting lipid fluidity, permeability and membrane function (Dianzani, 1993; Nicolson et al., 1977; Subczynski & Wisniewska, 2000). One of the most important events caused by ROS/RNS damage is loss of electron transport function, and this appears to be related to mitochondrial membrane lipid peroxidation. Membrane oxidation induces permeability changes in mitochondria, and this can cause loss of mitochondrial transmembrane potential, an essential requirement of oxidative phosphorylation (Kanno et al., 2004; Radi et al., 1994).

Lipid Replacement Therapy (Nicolson, 2003; 2005; 2010) has been used to reverse the accumulation of damaged lipids in mitochondria and other cellular membranes. Lipid Replacement Therapy plus antioxidants can reverse ROS/RNS damage and increase mitochondrial function in certain fatiguing disorders, such as chronic fatigue, chronic fatigue syndrome and fibromyalgia syndrome. Lipid Replacement Therapy has been found to be effective in preventing ROS/RNS-associated changes and reversing mitochondrial damage and loss of function (reviewed in Nicolson, 2010; Nicolson & Ellithrope, 2006).

Lipid Replacement Therapy with unoxidized lipid and antioxidant supplements has been effective in replacement of damaged cellular and mitochondrial membrane phospholipids and other lipids that are essential structural and functional components of all biological membranes (reviewed in Nicolson, 2010; Nicolson & Ellithrope, 2003). NTFactor, a Lipid Replacement oral supplement containing phospholipids, phosphoglycolipids, cardiolipid precursors and other membrane lipids, has been used successfully in animal and clinical lipid replacement studies (Agadjanyan et al., 2003; Ellithorpe et al., 2003; Nicolson & Ellithorpe, 2006; Nicolson et al., 2010). NTFactor's encapsulated lipids are protected from oxidation in the gut and can be absorbed and transported into tissues via lipid carriers without oxidation. Once inside cells the membrane lipids naturally replace oxidized, damaged membrane lipids by natural diffusion, and carrier proteins pick up the damaged lipids for degradation, transport and excretion (Mansbach & Dowell, 2000).

In preclinical studies NTFactor has been used to reduce age-related functional damage. Using rodents Seidman et al. (2002) found that NTFactor prevented hearing loss associated with aging and shifted the threshold hearing from 35-40 dB in control, aged rodents to 13-17 dB. They also found that NTFactor preserved cochlear mitochondrial function and prevented aging-related mitochondrial DNA deletions found in the cochlear. Thus NTFactor was successful in preventing age-associated hearing loss and reducing mitochondrial damage and DNA deletions in rodents (Seidman et al. 2002).

In clinical studies Lipid Replacement Therapy has been used to reduce fatigue and protect cellular and mitochondrial membranes from oxidative damage by ROS/RNS (reviewed in Nicolson, 2003; 2005; 2010). A vitamin supplement mixture containing NTFactor was by used by Ellithorpe et al. (2003) in a study of patients with severe chronic fatigue and was found to reduce their fatigue by approximately 40.5% in 8 weeks. In these studies fatigue was monitored by use of the Piper Fatigue Scale to measure clinical fatigue and quality of life (Piper et al., 1987). In addition, in a subsequent study we examined the effects of NTFactor on fatigue and mitochondrial function in patients with chronic fatigue (Agadjanyan et al., 2003). Oral administration of NTFactor for 12 weeks resulted in a 35.5% reduction in fatigue and 26.8% increase in mitochondrial function; whereas after a 12-week wash-out period fatigue increased and mitochondrial function decreased back towards control levels (Agadjanyan et al., 2003). Thus in fatigued subjects dietary Lipid Replacement Therapy can significantly improve and even restore mitochondrial function and significantly decrease fatigue. Similar findings were observed in chronic fatigue syndrome and fibromyalgia syndrome patients (Nicolson & Ellithorpe, 2003). Recently a new formulation of NTFactor plus vitamins, minerals and other supplements resulted in a 36.8% reduction in fatigue within one week (Nicolson et al., 2010) (Table 1).


Table 1.

Effects of dietary Lipid Replacement supplement NTFactor on Piper Fatigue Scale scores.

10. Lipid replacement therapy in conjunction with cancer therapy

Lipid Replacement Therapy has been used to reduce the adverse effects of chemotherapy in cancer patients (Nicolson, 2010). For example, a vitamin-mineral mixture with NTFactor has been used in cancer patients to reduce some of most common adverse effects of cancer therapy, such as chemotherapy-induced fatigue, nausea, vomiting, malaise, diarrhea, headaches and other side effects (Colodny et al., 2000). In two studies on patients with advanced metastatic colon, pancreatic or rectal cancers receiving a 12-week chemotherapy treatment schedule of 5-florouracil/methotrexate/leukovorin Lipid Replacement Therapy was used to reduce adverse effects of chemotherapy.

In the first unblinded part of the clinical study the effectiveness of NTFactor in a vitamin-mineral mixture administered before and during chemotherapy was determined by examining signs and symptoms, and in particular, the side effects of therapy. A quality of life evaluation was conducted by a research nurse, and it was determined that patients on NTFactor supplementation experienced significantly fewer episodes of fatigue, nausea, diarrhea, constipation, skin changes, insomnia and other side effects (Colodny et al., 2000). In this open label trial 81% of patients demonstrated an overall improvement in quality of life parameters while on chemotherapy with Lipid Replacement Therapy (Colodny et al., 2000).

In the double-blinded, cross-over, placebo-controlled, randomized part of the study on advanced cancers the patients on chemotherapy plus Lipid Replacement Therapy showed improvements in signs/symptoms associated with the adverse effects of chemotherapy (Colodny et al., 2000). Adding Lipid Replacement resulted in improvements in the incidence of fatigue, nausea, diarrhea, impaired taste, constipation, insomnia and other quality of life indicators. Following cross-over from the placebo arm to the Lipid Replacement Therapy arm, 57-70% of patients on chemotherapy reported improvements in nausea, impaired taste, tiredness, appetite, sick feeling and other quality of life indicators (Colodny et al., 2000) (Table 2). This clinical trial and other data clearly demonstrated the usefulness of Lipid Replacement Therapy given during chemotherapy to reduce the adverse effects of cancer therapy (Nicolson, 2010).


Table 2.

Effects of Propax with NTFactor on the adverse effects of chemotherapy in a cross-over trial.

11. Summary – Cancer-associated fatigue and its treatment

Nutritional supplements have been used in a variety of diseases to provide patients with a natural, safe alternative to pharmacological drugs. In patients with cancer nutritional supplements are often used for specific purposes or to improve quality of life. For example, cancer-associated fatigue is one of the most common symptoms in all forms and stages of cancer, but few patients receive assistance for their fatigue. Cancer-associated fatigue is associated with cellular oxidative stress, and during cancer therapy excess drug-induced oxidative stress can cause a number of adverse effects, including: fatigue, nausea, vomiting and more serious effects. Cancer-associated fatigue and the adverse effects of cancer therapy can be reduced with Lipid Replacement Therapy, a natural lipid supplement formulation that replaces damaged membrane lipids along with providing antioxidants and enzymatic cofactors. Administering dietary Lipid Replacement Therapy can reduce oxidative membrane damage and restore mitochondrial and other cellular functions. Recent clinical trials using cancer and non-cancer patients with chronic fatigue have shown the benefits of specific Lipid Replacement Therapy nutritional lipid supplements in reducing fatigue and restoring mitochondrial function.


1 - S. Abidi, A. Ali, 1999 Role of oxygen free radicals in the pathogenesis and etiology of cancer, Cancer Letters 142 19 .
2 - R. Aeschbach, J. Loliger, B. C. Scott, et al. 1994 Antioxidant actions of thymol, carvacrol, 6-gingerol, zingerone and hydroxytyrosol, Food Chemistry and Toxicology 32 3136 .
3 - M. Agadjanyan, V. Vasilevko, A. Ghochikyan, et al. 2003 Nutritional supplement (NTFactor) restores mitochondrial function and reduces moderately severe fatigue in aged subjects, Journal of Chronic Fatigue Syndrome 11 3 2326 .
4 - K. Ahlberg, T. Ekman, F. Gaston-Johansson, V. Mock, 2003 Assessment and management of cancer-related fatigue in adults, The Lancet 362 9384 640650 .
5 - L. M. Arnold, 2008 Understanding fatigue in major depressive disorder and other medical disorders, Psychosomatics 49 185190 .
6 - N. R. Asal, D. R. Risser, S. Kadamani, et al. 1990 Risk factors in renal cell carcinoma. I. Methodology, demographics, tobacco beverage use and obesity, Cancer Detection and Prevention 11 359377 .
7 - A. Aydin, Z. Arsova-Sarafinovska, A. Sayal, et al. 2006 Oxidative stress and antioxidant status in non-metastatic prostate cancer and benign prostate hyperplasia, Clinical Biochemistry 39 176179 .
8 - A. K. Balin, D. B. P. Goodman, H. Rasmussen, et al. 1978 Oxygen-sensitive stages of the cell cycle of human diploid cells, Journal of Cell Biology 78 390400 .
9 - D. A. Barber, S. R. Harris, 1994 Oxygen free radicals and antioxidants: a review, American Pharmacology 34 2635 .
10 - H. Bartsch, J. Nair, 2004 Oxidative stress and lipid peroxidation-driven DNA-lesions in inflammation driven carcinogenesis, Cancer Detection and Prevention 28 385391 .
11 - K. Batcioglu, N. Mehmet, I. C. Ozturk, et al. 2006 Lipid peroxidation and antioxidant status in stomach cancer, Cancer Investigation 24 1821 .
12 - C. M. Bender, S. J. Engberg, H. S. Donovan, et al. 2008 Symptom clusters in adults with chronic health problems and cancer as a co-morbidity, Oncology Nursing Forum 35: E1 -E11.
13 - D. J. Betteridge, 2000 What is oxidative stress? Metabolism 49(suppl 1): 3-8.
14 - T. Borneman, B. F. Piper, V. C. Sun, et al. 2007 Implementing the fatigue guidelines at one NCCN member institution: process and outcomes, Journal of the National Comprehensive Cancer Network 5 10921101 .
15 - D. M. Brizel, 2007 Pharmacologic approaches to radiation protection, Journal of Clinical Oncology 25 40844089 .
16 - L. F. Brown, K. Kroenke, 2009 Cancer-related fatigue and its association with depression and anxiety: a systematic review, Psychosomatics 50 440447 .
17 - N. S. Brown, R. Bicknell, 2001 Hypoxia and oxidative stress in breast cancer. Oxidative stress: its effects on the growth, metastatic potential and response to therapy of breast cancer, Breast Cancer Research 3 323327 .
18 - R. Buckingham, J. Fitt, J. Sitzia, 1997 Patients’ experience of chemotherapy: side-effects of carboplatin in the treatment of carcinoma of the ovary, European Journal of Cancer Care 6 5971 .
19 - B. R. Cassileth, M. Heitzer, K. Wesa, 2009 The public health impact of herbs and nutritional supplements, Pharmaceutical Biology 47 761767 .
20 - L. Castro, B. A. Freeman, 2001 Reactive oxygen species in human health and disease, Nutrition 17 295307 .
21 - D. Cella, K. Davis, W. Breitbart, et al. 2001 Cancer-related fatigue: prevalence of proposed diagnostic criteria in a United States sample of cancer survivors, Journal of Clinical Oncology 19 33853391 .
22 - J. Chandra, A. Samali, S. Orrenius, 2000 Triggering and modulation of apoptosis by oxidative stress. Free Radical Biology and Medicine 29 323333 .
23 - L. Colodny, K. Lynch, C. Farber, et al. 2000 Results of a study to evaluate the use of Propax to reduce adverse effects of chemotherapy, Journal of the American Nutraceutical Association 2 1 1725 .
24 - K. A. Conklin, 2000 Dietary antioxidants during cancer chemotherapy: impact on chemotherapeutic effectiveness and development of side effects, Nutrition and Cancer 37 118 .
25 - K. A. Conklin, 2004 Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness, Integrated Cancer Therapies 3 294300 .
26 - K. A. Conklin, 2005 Coenzyme Q10 for prevention of anthracycline-induced cardiotoxicity, Integrated Cancer Therapies 4 110130 .
27 - E. P. Cortes, M. Gupta, C. Chou, et al. 1978 Adriamycin cardiotoxicity: early detection by systolic time interval and possible prevention by coenzyme Q10, Cancer Treatment Reports 62 887891 .
28 - G. A. Curt, W. Breitbart, D. Cella, et al. 2000 Impact of cancer-related fatigue on the lives of patients: new findings from The Fatigue Coalition, The Oncologist 5 353360 .
29 - K. J. A. Davies, J. H. Doroshow, 1986 Redox cycling of anthracyclines by cardiac mitochondria. I. Anthracycline radical formation by NADH dehydrogenase, Journal of Biological Chemistry 261 30603067 .
30 - M. U. Dianzani, 1993 Lipid peroxidation and cancer, Critical Reviews in Oncology and Hematology 15 125147 .
31 - N. Domae, H. Sawada, E. Matsuyama, et al. 1981 Cardiomyopathy and other chronic toxic effects induced in rabbits by doxorubicin and possible prevention by coenzyme Q10, Cancer Treatment Reports 65 7991 .
32 - J. H. Doroshow, K. J. A. Davies, 1986 Redox cycling of anthracyclines by cardiac mitochondria. II. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical, Journal of Biological Chemistry 261 30683074 .
33 - C. Doyle, L. H. Kushi, T. Byers, et al. 2006 Nutrition ad physical activity during and after cancer treatment: an American Cancer Society guide for informed choices, CA Cancer Journal 56 323353 .
34 - D. Dreher, A. F. Junod, 1996 Role of oxygen free radicals in cancer development, European Journal of Cancer 32A: 3038 .
35 - S. Eaton, R. Skinner, J. P. Hale, et al. 2000 Plasma coenzyme Q10 in children and adolescents undergoing doxorubicin therapy, Clinica Chimica Acta 302 19 .
36 - R. R. Ellithorpe, R. Settineri, G. L. Nicolson, 2003 Reduction of fatigue by use of a dietary supplement containing glycophospholipids, Journal of the American Nutraceutical Association 6 1 2328 .
37 - M. W. Epperly, J. E. Gretton, C. A. Sikora, et al. 2003 Mitochondrial localization of superoxide dismutase is required for decreasing radiation-induced cellular damage, Radiation Research 160 568578 .
38 - C. P. Escalante, M. A. Kallen, R. U. Valdres, et al. 2011 Outcomes of a cancer-related fatigue clinic in a comprehensive cancer center, Journal of Pain and Symptom Mangement in press.
39 - L. E. Feinendegen, M. Pollycove, R. D. Neumann, 2007 Whole-body responses to low-level radiation exposure: New concepts in mammalian radiobiology, Experimental Hematology 35 3746 .
40 - S. Felle, P. Mecocci, G. Fano, et al. 2000 Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome, Free Radical Biology and Medicine 29 12521259 .
41 - T. Fojo, 2001 Cancer, DNA repair mechanisms, and resistance to chemotherapy, Journal of the National Cancer Institute 93 14341436 .
42 - I. Fridovich, 1995 Superoxide radical and superoxide dismutases, Annual Review of Biochemistry 64 97112 .
43 - M. Gago-Dominguez, J. E. Castelao, J. M. Yuan, et al. 2002 Lipid peroxidation: a novel and unifying concept of the etiology of renal cell carcinoma, Cancer Causes and Control 13 287293 .
44 - T. Gansler, C. Kaw, C. Crammer, T. Smith, 2008 A population-based study of prevalence of complementary methods use by cancer survivors, GanslerT.KawC.CrammerC.SmithT. (2008). A population-based study of prevalence of complementary methods use by cancer survivors, Cancer . 113 10481057 .
45 - S. Ghaffari, 2008 Oxidative stress in the regulation of normal and neoplastic hematopoiesis, Antioxidation and Redox Signaling 10 19231940 .
46 - L. Gille, H. Nohl, 1997 Analyses of the molecular mechanism of Adriamycin-induced cardiotoxicity, Free Radical Biology and Medicine 23 775782 .
47 - E. Giovannucci, A. T. Chan, 2010 Role of vitamin and mineral supplementation and aspirin use in cancer survivors, Journal of Clinical Oncology 28 40814085 .
48 - B. Given, C. Given, F. Azzouz, M. Stommel, 2001 Physical functioning of elderly cancer patients prior to diagnosis and following initial treatment, Nursing Research 50 222232 .
49 - M. J. Gonzalez, 1992 Lipid peroxidation and tumor growth: an inverse relationship, Medical Hypotheses 38 106110 .
50 - J. S. Greenberger, V. E. Kagan, L. Pearce, et al. 2001 Modulation of redox signal transduction pathways in the treatment of cancer, Antioxidants and Redox Signaling 3 347359 .
51 - H. B. Gutstein, 2001 The biological basis for fatigue. Cancer 92 16781683 .
52 - B. Halliwell, 1996 Oxidative stress, nutrition and health, Free Radical Research 25 5774 .
53 - M. B. Hampton, B. Fadeel, S. Orrenius, 1998 Redox regulation of the caspases during apoptosis, Annals of the New York Academy of Science 854 328335 .
54 - S. Hauptlorenz, H. Esterbauer, W. Moll, et al. 1985 Effects of the lipid peroxidation product 4-hydroxynonenal and related aldehydes on proliferation and viability of cultured Ehrlich ascites tumor cells, Biochemical Pharmacology 34 38033809 .
55 - M. Hofman, J. L. Ryan, C. D. Figueroa-Moseley, et al. 2007 Cancer-related fatigue: the scale of the problem, The Oncologist 12 410 .
56 - H. Huang, K. G. Manton, 2004 The role of oxidative damage in mitochondria during aging: a review, Frontiers in Bioscience 9 11001117 .
57 - D. Iarussi, U. Auricchio, A. Agretto, et al. 1994 Protective effect of coenzyme Q10 on anthracyclines cardiotoxicity: control study in children with acute lymphoblastic leukemia and non-Hodgkin lymphoma, Molecular Aspects of Medicine 15: S207 -S212.
58 - E. Isenring, G. Cross, E. Kellett, B. Koczwara, 2010 Nutritional status and iformation needs of medical oncology patients receiving treatment at an Australian public hospital, Nutrition and Cancer 62 220228 .
59 - G. C. Jagetia, G. K. Rajanikant, S. K. Rao, et al. 2003 Alteration in the glutathione, glutathione peroxidase, superoxide dismutase and lipid peroxidation by ascorbic acid in the skin of mice exposed to fractionated gamma radiation, Clinica Chimica Acta 332 111121 .
60 - P. Jaruga, T. H. Zastawny, J. Skokowski, et al. 1992 Oxidative DNA base damage and antioxidant enzyme activities in human lung cancer, FEBS Letters 341 5964 .
61 - T. M. Johnson, Z. X. Yu, V. J. Ferrans, et al. 1996 Reactive oxygen species are downstream mediators of 53 apoptosis, Proceedings of the National Academy of Science USA 93: 11848-11852.
62 - W. V. Judy, J. H. Hall, W. Dugan, et al. 1984 Coenzyme Q10 reduction of Adriamycin cardiotoxicity, in Folkers, K. & Yamamura, Y. (eds). Biomedical and Clinical Aspects of Coenzyme Q, 4 Amsterdam:Elsevier/North-Holland Biomedical Press, 231241 .
63 - D. H. Kang, 2002 Oxidative stress, DNA damage and breast cancer, AACN Clinical 13 13 540549 .
64 - T. Kanno, E. E. Sato, S. Muranaka, et al. 2004 Oxidative stress underlies the mechanism for Ca(2+)-induced permeability transition of mitochondria, Free Radical Research 38 2735 .
65 - J. Karlsson, K. Folkers, H. Astrom, et al. 1986 Effect of Adriamycin on heart and skeletal muscle coenzyme Q10 (CoQ10) in man, in Folkers, K. & Yamamura, Y. (eds), Biomedical and Clinical Aspects of Coenzyme Q, 5 Amsterdam:Elsevier/North-Holland Biomedical Press, 241245 .
66 - J. P. Kehrer, 1993 Free radicals and mediators of tissue injury and disease, Critical Reviews in Toxicology 23 2148 .
67 - J. E. Klaunig, L. M. Kamendulis, 2004 The role of oxidative stress in carcinogenesis, Annual Review of Pharmacology and Toxicology 44 239267 .
68 - K. Kroenke, D. R. Wood, A. D. Mangelsdorff, et al. 1988 Chronic fatigue in primary care. Prevalence, patient characteristics, and outcome, JAMA 260 929934 .
69 - S. Kurata, 2000 Selective activation of 38 MAPK cascade and mitotic arrest caused by low level oxidative stress, Journal of Biological Chemistry 275: 23413-23416.
70 - J. K. Leach, S. M. Black, R. K. Schmidt-Ullrich, R. B. Mikkelsen, 2002 Activation of constitutive nitric-oxide synthase activity is an early signaling event induced by ionizing radiation. Journal of Biological Chemistry 277 1540015406 .
71 - A. L. Lehninger, 1951 Phosphorylation coupled to oxidation of dihydrodiphosphopyridine nucleotide, Journal of Biological Chemistry 190 345359 .
72 - M. Levy, 2008 Cancer fatigue: a review for psychiatrists, General Hospital Psychiatry 30 233244 .
73 - L. Liu, M. R. Marler, B. A. Parker, et al. 2005 The relationship between fatigue and light exposure during chemotherapy, Supportive Care in Cancer 13 10101017 .
74 - A. C. Logan, C. Wong, 2001 Chronic fatigue syndrome: oxidative stress and dietary modifications, Alternative Medicine Reviews 6 450459 .
75 - Y. K. Loke, D. Price, S. Derry, et al. 2006 Case reports of suspected adverse drug reactions-systematic literature survey of follow-up, British Medical Journal 232 335339 .
76 - M. Maes, F. N. Twisk, 2009 Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS, NeuroEndocrinology Letters 30 677693 .
77 - M. Maes, 2009 Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms, Current Opinions in Psychiatry 22 7583 .
78 - S. Manoharan, K. Kolanjiappan, K. Suresh, et al. 2005 Lipid peroxidation and antioxidants status in patients with oral squamous cell carcinoma, Indian Journal of Medical Research 122 529534 .
79 - C. M. Mansbach, R. Dowell, 2000 Effect of increasing lipid loads on the ability of the endoplasmic reticulum to transport lipid to the Golgi, Journal of Lipid Research 41 605612 .
80 - y. Manuel, B. Keenoy, G. Moorkens, J. Vertommen, I. De Leeuw, 2001 Antioxidant status and lipoprotein peroxidation in chronic fatigue syndrome, Life Science 68 20372049 .
81 - E. F. Manzullo, C. P. Escalante, 2002 Research into fatigue, Hematology Oncology Clinics of North America 16 619628 .
82 - L. J. Marnett, 2000 Oxyradicals and DNA damage, Carcinogenesis 21 361370 .
83 - G. R. Marrow, 2007 Cancer-related fatigue: causes, consequences and management, The Oncologist 12(suppl 1): 1-3.
84 - E. Mc Donald, A. S. David, A. J. Pelosi, A. H. Mann, 1993 Chronic fatigue in primary care attendees, Psycholgical Medicine 23 987998 .
85 - P. E. Miller, J. J. Vasey, P. F. Short, T. J. Hartman, 2009 Dietary supplement use in adult cancer survivors, Oncology Nursing Forum 36 1 6168 .
86 - O. Milton, A. Richardson, M. Sharpe, et al. 2008 A systematic review and meta-analysis of the pharmacological treatment of cancer-related fatigue, Journal of the National Cancer Institute 100 112 .
87 - J. D. Morrison, 1980 Fatigue as a presenting complaint in family practice, Journal of Family Practice 10 795801 .
88 - K. M. Mustian, G. R. Morrow, J. K. Carroll, et al. 2007 Integrative nonpharmacological behavioral interventions for the management of cancer-related fatigue, The Oncologist 12(Suppl. 1): 52-67.
89 - G. L. Nicolson, K. A. Conklin, 2008 Reversing mitochondrial dysfunction, fatigue and the adverse effects of chemotherapy of metastatic disease by Molecular Replacement Therapy, Clinical and Experimental Metastasis 25 161169 .
90 - G. L. Nicolson, R. Ellithrope, 2006 Lipid replacement and antioxidant nutritional therapy for restoring mitochondrial function and reducing fatigue in chronic fatigue syndrome and other fatiguing illnesses, Journal of Chronic Fatigue Syndrome 13 1 5768 .
91 - G. L. Nicolson, 2003 Lipid replacement as an adjunct to therapy for chronic fatigue, anti-aging and restoration of mitochondrial function, Journal of the American Nutraceutical Association 6 3 2228 .
92 - G. L. Nicolson, 2005 Lipid replacement/antioxidant therapy as an adjunct supplement to reduce the adverse effects of cancer therapy and restore mitochondrial function, Pathology and Oncology Research 11 139144 .
93 - G. L. Nicolson, 2010 Lipid replacement therapy: a nutraceutical approach for reducing cancer-associated fatigue and the adverse effects of cancer therapy while restoring mitochondrial function. Cancer & Metastasis Reviews 29 543552 .
94 - G. L. Nicolson, R. R. Ellithorpe, C. Ayson-Mitchell, et al. 2010 Lipid Replacement Therapy with a glycophospholipid-antioxidant-vitamin formulation significantly reduces fatigue within one week, Journal of the American Nutraceutical Association 13 1 1115 .
95 - G. L. Nicolson, G. Poste, T. Ji, 1977 Dynamic aspects of cell membrane organization, Cell Surface Reviews 3 173 .
96 - H. Nohl, 1987 Demonstration of the existence of an organo-specific NADH dehydrogenase in heart mitochondria, European Journal of Biochemistry 169 585591 .
97 - T. Otamiri, R. Sjodahl, 1989 Increased lipid peroxidation in malignant tissues of patients with colorectal cancer, OtamiriT.SjodahlR. (1989). Increased lipid peroxidation in malignant tissues of patients with colorectal cancer, Cancer . 64 422425 .
98 - G. Oxdemirler, H. Pabucçoglu, T. Bulut, et al. 1989 Increased lipoperoxide levels and antioxidant system in colorectal cancer, Journal of Cancer Research and Clinical Oncology 124 555559 .
99 - M. L. Pall, 2000 Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome, Medical Hypotheses 54 115125 .
100 - C. M. Palmeira, J. Serrano, D. W. Kuehl, et al. 1997 Preferential oxidation of cardiac mitochondrial DNA following acute intoxication with doxorubicin, Biochimica et Biophysica Acta 1321 101106 .
101 - L. C. Papadopoulou, A. S. Tsiftsoglou, 1996 Effects of hemin on apoptosis, suppression of cytochrome C oxidase gene expression, and bone-marrow toxicity induced by doxorubicin, Biochemical Pharmacology 52 713722 .
102 - B. F. Piper, A. M. Linsey, M. J. Dodd, 1987 Fatigue mechanism in cancer, Oncology Nursing Forum 14 1723 .
103 - K. N. Prasad, W. C. Cole, B. Kumar, et al. 2001 Scientific rationale for using high-dose multiple micronutrients as an adjunct to standard and experimental cancer therapies, Journal of the American College of Nutrition 20: 450S 463S 3B - 453S.
104 - G. Prue, J. Rankin, J. Allen, et al. 2006 Cancer-related fatigue: a critical appraisal, European Journal of Cancer 42 846863 .
105 - R. Radi, M. Rodriguez, L. Castro, et al. 1994 Inhibition of mitochondrial electronic transport by peroxynitrite, Archives of Biochemistry and Biophysics 308 8995 .
106 - U. F. Rasmussen, H. N. Rasmussen, 1985 The NADH oxidase system (external) of muscle mitochondria and its role in the oxidation of cytoplasmic NADH, Biochemical Journal 229 632641 .
107 - G. Ray, S. Batra, N. K. Shukla, et al. 2000 Lipid peroxidation, free radical production and antioxidant status in breast cancer, Breast Cancer Research and Treatment 59 163170 .
108 - D. Respini, P. B. Jacobsen, C. Thors, et al. 2003 The prevalence and correlates of fatigue in older cancer patients, Critical Reviews in Oncology and Hematology 47 273279 .
109 - R. S. Richards, T. K. Roberts, N. R. Mc Gregor, et al. 2000 Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome, Redox Reports 5 3541 .
110 - J. L. Ryan, J. K. Carroll, E. P. Ryan, et al. 2007 Mechanisms of cancer-related fatigue, The Oncologist 12(Supp. 1): 2234 .
111 - I. Sabbarova, A. Kanai, 2007 Targeted delivery of radioprotective agents to mitochondria, Molecular Interventions 8 295302 .
112 - R. E. Schackelford, W. K. Kaufmann, R. S. Paules, 2000 Oxidative stress and cell cycle checkpoint function, Free Radical Biology and Medicine 28 13871404 .
113 - J. L. Schwartz, 1996 The dual roles of nutrients as antioxidants and prooxidants: their effects on tumor cell growth, Journal of Nutrition 126: 1221S7S.
114 - M. Seidman, M. J. Khan, W. X. Tang, et al. 2002 Influence of lecithin on mitochondrial DNA and age-related hearing loss, Otolaryngology and Head and Neck Surgery 127 138144 .
115 - H. E. Seifried, S. S. Mc Donald, D. E. Anderson, et al. 2003 The antioxidant conundrum in cancer, Cancer Research 61 42954298 .
116 - D. N. Seril, J. Liao, G. Y. Yang, et al. 2003 Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models, SerilD. N.LiaoJ.YangG. al. (2003). Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models, Carcinogenesis . 34 353362 .
117 - J. Serrano, C. M. Palmeira, D. W. Kuehl, et al. 1999 Cardioselective and cumulative oxidation of mitochondrial DNA following subchronic doxorubicin administration, Biochimica et Biophysica Acta 1411 201205 .
118 - E. Shacter, J. A. Williams, R. M. Hinson, et al. 2000 Oxidative stress interferes with cancer chemotherapy: inhibition of lymphoma cell apoptosis and phagocytosis, Blood 96 307313 .
119 - S. C. Sikka, 2003 Role of oxidative stress response elements and antioxidants in prostate cancer pathobiology and chemoprevention-a mechanistic approach, Current Medicinal Chemistry 10 26792692 .
120 - E. M. A. Smets, B. Garssen, A. Cull, et al. 1996 Applications of the Multidimensional Fatigue Inventory (MFI-20) in cancer patients receiving radiotherapy, British Journal of Cancer 73 241245 .
121 - A. Sood, T. J. Moynihan, 2005 Cancer-related fatigue: an update, Current Oncology Reports 7 277282 .
122 - E. Stadtman, 2002 Introduction to serial reviews on oxidatively modified proteins in aging and disease, Free Radical Biology and Medicine 32: 789.
123 - P. Stone, J. Hardy, R. Huddart, et al. 2000 Fatigue in patients with prostate cancer receiving hormone therapy, European Journal of Cancer 36 11341141 .
124 - A. Ströhle, K. Zänker, A. Hahn, 2010 Nutrition in oncology: the case of micronutrients, Oncology Reports 24 815828 .
125 - W. K. Subczynski, A. Wisniewska, 2000 Physical properties of lipid bilayer membranes: relevance to membrane biological functions, Acta Biochimica Polonica 47 613625 .
126 - Y. Sun, 1990 Free radicals, antioxidant enzymes and carcinogenesis, Free Radical Biology and Medicine 8 583599 .
127 - T. Tanaka, 1994 Cancer chemoprevention by natural products, Oncology Reports 1 11391155 .
128 - F. Tas, H. Hansel, A. Belce, et al. 2005 Oxidative stress in breast cancer, Medical Oncology 22 1115 .
129 - S. Toyokuni, K. Okamoto, J. Yodio, et al. 1995 Persistent oxidative stress in cancer, FEBS Letters 358 13 .
130 - T. Usui, H. Ishikura, Y. Izumi, et al. 1982 Possible prevention from the progression of cardiotoxicity in Adriamycin-treated rabbits by coenzyme Q10, Toxicology Letters 12 7582 .
131 - C. M. Velicer, C. M. Ulrich, 2008 Vitamin and mineral supplement use among U.S. adults after cancer diagnosis: a systematic review, Journal of Clinical Oncology 26 665673 .
132 - N. Vogelzang, W. Breitbart, D. Cella, et al. 1997 Patient caregiver and oncologist perceptions of cancer-related fatigue: results of a tripart assessment survey, Seminars in Hematology 34 EOF12 EOF .
133 - Roenn. J. H. Von, J. A. Paice, 2005 Control of common, non-pain cancer symptoms, Seminars in Oncology 32 200210 .
134 - T. Watson, V. Mock, 2004 Exercise as an intervention for cancer-related fatigue, Physical Therapy 84 736743 .
135 - Q. Wei, M. L. Frazier, B. Levin, 2000 DNA repair: a double edge sword, Journal of the National Cancer Institute 92 440441 .
136 - Y. H. Wei, H. C. Lee, 2002 Oxidative stress, mitochondrial DNA mutation and impairment of antioxidant enzymes in aging, Experimental Biology and Medicine 227 671682 .
137 - P. C. Zee, S. Acoli-Isreal, 2009 Does effective management of sleep disorders reduce cancer-related fatigue? Drugs 69(Suppl. 2): 29-41.
138 - W. Zhen, C. J. Link, P. M. O’Connor, et al. 1992 Increased gene-specific repair of cisplatin interstrand cross-links in cisplatin-resistant human ovarian cancer cell lines, Molecular and Cellular Biology 12 36893698 .