**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;

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

**4. Cancer therapy causes excess oxidative stress and severe fatigue** 

to molecular oxygen with the formation of superoxide radicals (Conklin, 2000; 2004).

radicals (Betteridge, 2000; Conklin, 2000).

Kurata, 2000; Schackelford et al., 2000).

antineoplastic agents (Conklin, 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

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;

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

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).
