Open Access is an initiative that aims to make scientific research freely available to all. To date our community has made over 100 million downloads. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. As PhD students, we found it difficult to access the research we needed, so we decided to create a new Open Access publisher that levels the playing field for scientists across the world. How? By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers.
We are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including Nobel Prize winners and some of the world’s most-cited researchers. Publishing on IntechOpen allows authors to earn citations and find new collaborators, meaning more people see your work not only from your own field of study, but from other related fields too.
To purchase hard copies of this book, please contact the representative in India:
CBS Publishers & Distributors Pvt. Ltd.
www.cbspd.com
|
customercare@cbspd.com
Department of Molecular Pathology,The Institute for Molecular Medicine, Huntington Beach, California, USA
*Address all correspondence to:
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.
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).
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).
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).
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).
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).
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.
References
1.AbidiS.AliA.1999 Role of oxygen free radicals in the pathogenesis and etiology of cancer, Cancer Letters14219 .
2.AeschbachR.LoligerJ.ScottB. C.et al.1994Antioxidant actions of thymol, carvacrol, 6-gingerol, zingerone and hydroxytyrosol,Food Chemistry and Toxicology323136 .
3.AgadjanyanM.VasilevkoV.GhochikyanA.et al.2003 Nutritional supplement (NTFactor) restores mitochondrial function and reduces moderately severe fatigue in aged subjects, Journal of Chronic Fatigue Syndrome1132326 .
4.AhlbergK.EkmanT.Gaston-JohanssonF.MockV.2003Assessment and management of cancer-related fatigue in adults, The Lancet3629384640650 .
5.ArnoldL. M.2008Understanding fatigue in major depressive disorder and other medical disorders, Psychosomatics49185190 .
6.AsalN. R.RisserD. R.KadamaniS.et al.1990Risk factors in renal cell carcinoma. I. Methodology, demographics, tobacco beverage use and obesity,Cancer Detection and Prevention11359377 .
7.AydinA.Arsova-SarafinovskaZ.SayalA.et al.2006Oxidative stress and antioxidant status in non-metastatic prostate cancer and benign prostate hyperplasia,Clinical Biochemistry39176179 .
8.BalinA. K.GoodmanD. B. P.RasmussenH.et al.1978Oxygen-sensitive stages of the cell cycle of human diploid cells, Journal of Cell Biology78390400 .
9.BarberD. A.HarrisS. R.1994Oxygen free radicals and antioxidants: a review,American Pharmacology342635 .
10.BartschH.NairJ.2004Oxidative stress and lipid peroxidation-driven DNA-lesions in inflammation driven carcinogenesis,Cancer Detection and Prevention28385391 .
11.BatciogluK.MehmetN.OzturkI. C.et al.2006Lipid peroxidation and antioxidant status in stomach cancer, Cancer Investigation241821 .
12.BenderC. M.EngbergS. J.DonovanH. S.et al.2008 Symptom clusters in adults with chronic health problems and cancer as a co-morbidity, Oncology Nursing Forum 35: E1 -E11.
13.BetteridgeD. J.2000 What is oxidative stress? Metabolism 49(suppl 1): 3-8.
14.BornemanT.PiperB. F.SunV. C.et al.2007Implementing the fatigue guidelines at one NCCN member institution: process and outcomes, Journal of the National Comprehensive Cancer Network 510921101 .
15.BrizelD. M.2007Pharmacologic approaches to radiation protection, Journal of Clinical Oncology2540844089 .
16.BrownL. F.KroenkeK.2009Cancer-related fatigue and its association with depression and anxiety: a systematic review,Psychosomatics50440447 .
17.BrownN. S.BicknellR.2001Hypoxia and oxidative stress in breast cancer. Oxidative stress: its effects on the growth, metastatic potential and response to therapy of breast cancer,Breast Cancer Research3323327 .
18.BuckinghamR.FittJ.SitziaJ.1997 Patients’ experience of chemotherapy: side-effects of carboplatin in the treatment of carcinoma of the ovary, European Journal of Cancer Care65971 .
19.CassilethB. R.HeitzerM.WesaK.2009The public health impact of herbs and nutritional supplements, Pharmaceutical Biology47761767 .
20.CastroL.FreemanB. A.2001Reactive oxygen species in human health and disease, Nutrition17295307 .
21.CellaD.DavisK.BreitbartW.et al.2001Cancer-related fatigue: prevalence of proposed diagnostic criteria in a United States sample of cancer survivors,Journal of Clinical Oncology1933853391 .
22.ChandraJ.SamaliA.OrreniusS.2000Triggering and modulation of apoptosis by oxidative stress.Free Radical Biology and Medicine29323333 .
23.ColodnyL.LynchK.FarberC.et al.2000 Results of a study to evaluate the use of Propax to reduce adverse effects of chemotherapy, Journal of the American Nutraceutical Association211725 .
24.ConklinK. A.2000Dietary antioxidants during cancer chemotherapy: impact on chemotherapeutic effectiveness and development of side effects,Nutrition and Cancer37118 .
25.ConklinK. A.2004Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness, Integrated Cancer Therapies3294300 .
26.ConklinK. A.2005Coenzyme Q10 for prevention of anthracycline-induced cardiotoxicity, Integrated Cancer Therapies4110130 .
27.CortesE. P.GuptaM.ChouC.et al.1978Adriamycin cardiotoxicity: early detection by systolic time interval and possible prevention by coenzyme Q10,Cancer Treatment Reports62887891 .
28.CurtG. A.BreitbartW.CellaD.et al.2000Impact of cancer-related fatigue on the lives of patients: new findings from The Fatigue Coalition,The Oncologist5353360 .
29.DaviesK. J. A.DoroshowJ. H.1986Redox cycling of anthracyclines by cardiac mitochondria. I. Anthracycline radical formation by NADH dehydrogenase,Journal of Biological Chemistry26130603067 .
30.DianzaniM. U.1993Lipid peroxidation and cancer, Critical Reviews in Oncology and Hematology15125147 .
31.DomaeN.SawadaH.MatsuyamaE.et al.1981Cardiomyopathy and other chronic toxic effects induced in rabbits by doxorubicin and possible prevention by coenzyme Q10,Cancer Treatment Reports657991 .
32.DoroshowJ. H.DaviesK. J. A.1986Redox cycling of anthracyclines by cardiac mitochondria. II. Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical, Journal of Biological Chemistry26130683074 .
33.DoyleC.KushiL. H.ByersT.et al.2006 Nutrition ad physical activity during and after cancer treatment: an American Cancer Society guide for informed choices, CA Cancer Journal56323353 .
34.DreherD.JunodA. F.1996Role of oxygen free radicals in cancer development, European Journal of Cancer 32A: 3038 .
35.EatonS.SkinnerR.HaleJ. P.et al.2000Plasma coenzyme Q10 in children and adolescents undergoing doxorubicin therapy, Clinica Chimica Acta30219 .
36.EllithorpeR. R.SettineriR.NicolsonG. L.2003 Reduction of fatigue by use of a dietary supplement containing glycophospholipids, Journal of the American Nutraceutical Association612328 .
37.EpperlyM. W.GrettonJ. E.SikoraC. A.et al.2003Mitochondrial localization of superoxide dismutase is required for decreasing radiation-induced cellular damage, Radiation Research160568578 .
38.EscalanteC. P.KallenM. A.ValdresR. U.et al.2011Outcomes of a cancer-related fatigue clinic in a comprehensive cancer center, Journal of Pain and Symptom Mangement in press.
39.FeinendegenL. E.PollycoveM.NeumannR. D.2007Whole-body responses to low-level radiation exposure: New concepts in mammalian radiobiology, Experimental Hematology353746 .
40.FelleS.MecocciP.FanoG.et al.2000 Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome, Free Radical Biology and Medicine2912521259 .
41.FojoT.2001 Cancer, DNA repair mechanisms, and resistance to chemotherapy, Journal of the National Cancer Institute9314341436 .
42.FridovichI.1995Superoxide radical and superoxide dismutases,Annual Review of Biochemistry6497112 .
43.Gago-DominguezM.CastelaoJ. E.YuanJ. M.et al.2002Lipid peroxidation: a novel and unifying concept of the etiology of renal cell carcinoma, Cancer Causes and Control 13287293 .
44.GanslerT.KawC.CrammerC.SmithT.2008A 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 .11310481057 .
45.GhaffariS.2008Oxidative stress in the regulation of normal and neoplastic hematopoiesis, Antioxidation and Redox Signaling1019231940 .
46.GilleL.NohlH.1997Analyses of the molecular mechanism of Adriamycin-induced cardiotoxicity,Free Radical Biology and Medicine23775782 .
47.GiovannucciE.ChanA. T.2010Role of vitamin and mineral supplementation and aspirin use in cancer survivors, Journal of Clinical Oncology2840814085 .
48.GivenB.GivenC.AzzouzF.StommelM.2001Physical functioning of elderly cancer patients prior to diagnosis and following initial treatment,Nursing Research50222232 .
49.GonzalezM. J.1992Lipid peroxidation and tumor growth: an inverse relationship,Medical Hypotheses38106110 .
50.GreenbergerJ. S.KaganV. E.PearceL.et al.2001Modulation of redox signal transduction pathways in the treatment of cancer, Antioxidants and Redox Signaling3347359 .
51.GutsteinH. B.2001The biological basis for fatigue. Cancer9216781683 .
52.HalliwellB.1996 Oxidative stress, nutrition and health, Free Radical Research255774 .
53.HamptonM. B.FadeelB.OrreniusS.1998Redox regulation of the caspases during apoptosis,Annals of the New York Academy of Science854328335 .
54.HauptlorenzS.EsterbauerH.MollW.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 3438033809 .
55.HofmanM.RyanJ. L.Figueroa-MoseleyC. D.et al.2007Cancer-related fatigue: the scale of the problem,The Oncologist12410 .
56.HuangH.MantonK. G.2004The role of oxidative damage in mitochondria during aging: a review,Frontiers in Bioscience911001117 .
57.IarussiD.AuricchioU.AgrettoA.et al.1994Protective 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.IsenringE.CrossG.KellettE.KoczwaraB.2010 Nutritional status and iformation needs of medical oncology patients receiving treatment at an Australian public hospital, Nutrition and Cancer62220228 .
59.JagetiaG. C.RajanikantG. K.RaoS. K.et al.2003Alteration 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 Acta332111121 .
60.JarugaP.ZastawnyT. H.SkokowskiJ.et al.1992Oxidative DNA base damage and antioxidant enzyme activities in human lung cancer,FEBS Letters3415964 .
61.JohnsonT. M.YuZ. X.FerransV. J.et al.1996Reactive oxygen species are downstream mediators of 53 apoptosis, Proceedings of the National Academy of Science USA 93: 11848-11852.
62.JudyW. V.HallJ. H.DuganW.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.KangD. H.2002 Oxidative stress, DNA damage and breast cancer, AACN Clinical 1313540549 .
64.KannoT.SatoE. E.MuranakaS.et al.2004 Oxidative stress underlies the mechanism for Ca(2+)-induced permeability transition of mitochondria, Free Radical Research382735 .
65.KarlssonJ.FolkersK.AstromH.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.KehrerJ. P.1993Free radicals and mediators of tissue injury and disease, Critical Reviews in Toxicology232148 .
67.KlaunigJ. E.KamendulisL. M.2004The role of oxidative stress in carcinogenesis,Annual Review of Pharmacology and Toxicology44239267 .
68.KroenkeK.WoodD. R.MangelsdorffA. D.et al.1988Chronic fatigue in primary care. Prevalence, patient characteristics, and outcome,JAMA260929934 .
69.KurataS.2000Selective activation of 38 MAPK cascade and mitotic arrest caused by low level oxidative stress, Journal of Biological Chemistry 275: 23413-23416.
70.LeachJ. K.BlackS. M.Schmidt-UllrichR. K.MikkelsenR. B.2002Activation of constitutive nitric-oxide synthase activity is an early signaling event induced by ionizing radiation. Journal of Biological Chemistry2771540015406 .
71.LehningerA. L.1951Phosphorylation coupled to oxidation of dihydrodiphosphopyridine nucleotide,Journal of Biological Chemistry190345359 .
72.LevyM.2008Cancer fatigue: a review for psychiatrists, General Hospital Psychiatry30233244 .
73.LiuL.MarlerM. R.ParkerB. A.et al.2005The relationship between fatigue and light exposure during chemotherapy,Supportive Care in Cancer1310101017 .
74.LoganA. C.WongC.2001Chronic fatigue syndrome: oxidative stress and dietary modifications,Alternative Medicine Reviews6450459 .
75.LokeY. K.PriceD.DerryS.et al.2006Case reports of suspected adverse drug reactions-systematic literature survey of follow-up, British Medical Journal232335339 .
76.MaesM.TwiskF. N.2009Why 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 Letters30677693 .
77.MaesM.2009Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms, Current Opinions in Psychiatry227583 .
78.ManoharanS.KolanjiappanK.SureshK.et al.2005Lipid peroxidation and antioxidants status in patients with oral squamous cell carcinoma, Indian Journal of Medical Research122529534 .
79.MansbachC. M.DowellR.2000Effect of increasing lipid loads on the ability of the endoplasmic reticulum to transport lipid to the Golgi,Journal of Lipid Research41605612 .
80.Manuely.KeenoyB.MoorkensG.VertommenJ.De LeeuwI.2001Antioxidant status and lipoprotein peroxidation in chronic fatigue syndrome,Life Science6820372049 .
81.ManzulloE. F.EscalanteC. P.2002Research into fatigue,Hematology Oncology Clinics of North America16619628 .
82.MarnettL. J.2000Oxyradicals and DNA damage,Carcinogenesis21361370 .
83.MarrowG. R.2007 Cancer-related fatigue: causes, consequences and management, The Oncologist 12(suppl 1): 1-3.
84.Mc DonaldE.DavidA. S.PelosiA. J.MannA. H.1993 Chronic fatigue in primary care attendees, Psycholgical Medicine23987998 .
85.MillerP. E.VaseyJ. J.ShortP. F.HartmanT. J.2009Dietary supplement use in adult cancer survivors, Oncology Nursing Forum3616168 .
86.MiltonO.RichardsonA.SharpeM.et al.2008 A systematic review and meta-analysis of the pharmacological treatment of cancer-related fatigue, Journal of the National Cancer Institute100112 .
87.MorrisonJ. D.1980Fatigue as a presenting complaint in family practice,Journal of Family Practice10795801 .
88.MustianK. M.MorrowG. R.CarrollJ. K.et al.2007 Integrative nonpharmacological behavioral interventions for the management of cancer-related fatigue, The Oncologist 12(Suppl. 1): 52-67.
89.NicolsonG. L.ConklinK. A.2008Reversing mitochondrial dysfunction, fatigue and the adverse effects of chemotherapy of metastatic disease by Molecular Replacement Therapy, Clinical and Experimental Metastasis25161169 .
90.NicolsonG. L.EllithropeR.2006Lipid replacement and antioxidant nutritional therapy for restoring mitochondrial function and reducing fatigue in chronic fatigue syndrome and other fatiguing illnesses, Journal of Chronic Fatigue Syndrome1315768 .
91.NicolsonG. L.2003 Lipid replacement as an adjunct to therapy for chronic fatigue, anti-aging and restoration of mitochondrial function, Journal of the American Nutraceutical Association632228 .
92.NicolsonG. L.2005Lipid replacement/antioxidant therapy as an adjunct supplement to reduce the adverse effects of cancer therapy and restore mitochondrial function,Pathology and Oncology Research11139144 .
93.NicolsonG. L.2010Lipid replacement therapy: a nutraceutical approach for reducing cancer-associated fatigue and the adverse effects of cancer therapy while restoring mitochondrial function. Cancer & Metastasis Reviews29543552 .
94.NicolsonG. L.EllithorpeR. R.Ayson-MitchellC.et al.2010 Lipid Replacement Therapy with a glycophospholipid-antioxidant-vitamin formulation significantly reduces fatigue within one week, Journal of the American Nutraceutical Association1311115 .
96.NohlH.1987Demonstration of the existence of an organo-specific NADH dehydrogenase in heart mitochondria, European Journal of Biochemistry169585591 .
97.OtamiriT.SjodahlR.1989Increased 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 .64422425 .
98.OxdemirlerG.PabucçogluH.BulutT.et al.1989 Increased lipoperoxide levels and antioxidant system in colorectal cancer, Journal of Cancer Research and Clinical Oncology124555559 .
99.PallM. L.2000 Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome, Medical Hypotheses54115125 .
100.PalmeiraC. M.SerranoJ.KuehlD. W.et al.1997Preferential oxidation of cardiac mitochondrial DNA following acute intoxication with doxorubicin,Biochimica et Biophysica Acta1321101106 .
101.PapadopoulouL. C.TsiftsoglouA. S.1996Effects of hemin on apoptosis, suppression of cytochrome C oxidase gene expression, and bone-marrow toxicity induced by doxorubicin,Biochemical Pharmacology52713722 .
103.PrasadK. N.ColeW. C.KumarB.et al.2001Scientific 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.PrueG.RankinJ.AllenJ.et al.2006Cancer-related fatigue: a critical appraisal, European Journal of Cancer42846863 .
105.RadiR.RodriguezM.CastroL.et al.1994 Inhibition of mitochondrial electronic transport by peroxynitrite, Archives of Biochemistry and Biophysics3088995 .
106.RasmussenU. F.RasmussenH. N.1985The NADH oxidase system (external) of muscle mitochondria and its role in the oxidation of cytoplasmic NADH,Biochemical Journal229632641 .
107.RayG.BatraS.ShuklaN. K.et al.2000Lipid peroxidation, free radical production and antioxidant status in breast cancer,Breast Cancer Research and Treatment59163170 .
108.RespiniD.JacobsenP. B.ThorsC.et al.2003The prevalence and correlates of fatigue in older cancer patients,Critical Reviews in Oncology and Hematology47273279 .
109.RichardsR. S.RobertsT. K.Mc GregorN. R.et al.2000Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome,Redox Reports53541 .
111.SabbarovaI.KanaiA.2007 Targeted delivery of radioprotective agents to mitochondria, Molecular Interventions8295302 .
112.SchackelfordR. E.KaufmannW. K.PaulesR. S.2000 Oxidative stress and cell cycle checkpoint function, Free Radical Biology and Medicine2813871404 .
113.SchwartzJ. L.1996The dual roles of nutrients as antioxidants and prooxidants: their effects on tumor cell growth,Journal of Nutrition 126: 1221S7S.
114.SeidmanM.KhanM. J.TangW. X.et al.2002Influence of lecithin on mitochondrial DNA and age-related hearing loss, Otolaryngology and Head and Neck Surgery127138144 .
116.SerilD. N.LiaoJ.YangG. Y.et al.2003Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models, SerilD. N.LiaoJ.YangG. Y.et al. (2003). Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models, Carcinogenesis .34353362 .
117.SerranoJ.PalmeiraC. M.KuehlD. W.et al.1999Cardioselective and cumulative oxidation of mitochondrial DNA following subchronic doxorubicin administration,Biochimica et Biophysica Acta1411201205 .
118.ShacterE.WilliamsJ. A.HinsonR. M.et al.2000Oxidative stress interferes with cancer chemotherapy: inhibition of lymphoma cell apoptosis and phagocytosis,Blood96307313 .
119.SikkaS. C.2003Role of oxidative stress response elements and antioxidants in prostate cancer pathobiology and chemoprevention-a mechanistic approach,Current Medicinal Chemistry1026792692 .
120.SmetsE. M. A.GarssenB.CullA.et al.1996 Applications of the Multidimensional Fatigue Inventory (MFI-20) in cancer patients receiving radiotherapy, British Journal of Cancer73241245 .
121.SoodA.MoynihanT. J.2005Cancer-related fatigue: an update, Current Oncology Reports7277282 .
122.StadtmanE.2002Introduction to serial reviews on oxidatively modified proteins in aging and disease, Free Radical Biology and Medicine 32: 789.
123.StoneP.HardyJ.HuddartR.et al.2000Fatigue in patients with prostate cancer receiving hormone therapy, European Journal of Cancer3611341141 .
124.StröhleA.ZänkerK.HahnA.2010Nutrition in oncology: the case of micronutrients,Oncology Reports24815828 .
125.SubczynskiW. K.WisniewskaA.2000Physical properties of lipid bilayer membranes: relevance to membrane biological functions,Acta Biochimica Polonica47613625 .
126.SunY.1990 Free radicals, antioxidant enzymes and carcinogenesis, Free Radical Biology and Medicine8583599 .
127.TanakaT.1994Cancer chemoprevention by natural products,Oncology Reports111391155 .
128.TasF.HanselH.BelceA.et al.2005Oxidative stress in breast cancer, Medical Oncology221115 .
129.ToyokuniS.OkamotoK.YodioJ.et al.1995Persistent oxidative stress in cancer,FEBS Letters35813 .
130.UsuiT.IshikuraH.IzumiY.et al.1982Possible prevention from the progression of cardiotoxicity in Adriamycin-treated rabbits by coenzyme Q10,Toxicology Letters127582 .
131.VelicerC. M.UlrichC. M.2008 Vitamin and mineral supplement use among U.S. adults after cancer diagnosis: a systematic review, Journal of Clinical Oncology26665673 .
132.VogelzangN.BreitbartW.CellaD.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.VonRoenn. J. H.PaiceJ. A.2005 Control of common, non-pain cancer symptoms, Seminars in Oncology32200210 .
134.WatsonT.MockV.2004Exercise as an intervention for cancer-related fatigue,Physical Therapy84736743 .
135.WeiQ.FrazierM. L.LevinB.2000DNA repair: a double edge sword,Journal of the National Cancer Institute92440441 .
136.WeiY. H.LeeH. C.2002 Oxidative stress, mitochondrial DNA mutation and impairment of antioxidant enzymes in aging, Experimental Biology and Medicine227671682 .
137.ZeeP. C.Acoli-IsrealS.2009 Does effective management of sleep disorders reduce cancer-related fatigue? Drugs 69(Suppl. 2): 29-41.
138.ZhenW.LinkC. J.O’ConnorP. M.et al.1992Increased gene-specific repair of cisplatin interstrand cross-links in cisplatin-resistant human ovarian cancer cell lines,Molecular and Cellular Biology1236893698 .
Written By
Garth L. Nicolson
Submitted: 29 November 2010Published: 27 January 2012