Harman’s free radical theory hypothesized that diseases, such as cancer and aging, resulted from the random or “stochastic” accumulation of oxidative damage purportedly caused by EMODs, from environmental sources and from by-products of normal cellular metabolism. ^1-5 When investigators found that their results were not as predicted by the free radical theory, they either discounted their results or referred to them as a paradox. Countless examples of this are in the literature but can be best illustrated by the 1995 tome edited by Kelvin J.A. Davies and Fulvio Ursini entitled, THE OXYGEN PARADOX.

The alleged damaging derivatives of oxygen were defined as being inherently deleterious and harmful. However, this notion has been rebuffed by Howes. ⁶ Apoptosis, necrosis, and growth arrest have been shown to be regulated to a significant degree by prooxidant EMOD species. ^7-10 Apoptosis, in part, controls the neoplastic process as genetically damaged or mutated cells can be eliminated ^{by inducement of the apoptotic process. 11 Apoptosis involves caspases (cysteine proteases cleaving after particular aspartate residues), mitochondrial pathways and/or EMODs, which are usually, but not always, key components. 12 Many apoptosis-inducing agents function as prooxidants in vitro. 13}

Prooxidant EMOD generating agents have repeatedly been ^{shown to kill cancer cells selectively, while sparing normal cells and this tumoricidal action can be modified or blocked by antioxidants, which may accelerate cancer growth both in vitro and in vivo. 14-17 Since therapeutic agents (radiation therapy, chemotherapy or photodynamic therapy, PDT) work, to a considerable extent, by releasing prooxidant free radicals (EMODs), it is logical that antioxidants likely interfere with their action. EMOD levels and cellular redox tone appear to be uniquely exploitable targets in cancer chemoprevention via the stimulation or induction of cytoprotection in normal cells and/or the induction of apoptosis in transformed malignant cells.}

Yet, some believe that antioxidants may play a central role in apoptosis and cancer therapy. Some investigators have made claims that antioxidants can actually kill cancer cells and argue that antioxidants are beneficial during chemotherapy. A review on the use of antioxidants during chemotherapy, published in Cancer Treatment Reviews, was a collaborative effort led by Dr. Keith Block and researchers from the University of Illinois at Chicago and M.D. Anderson Cancer Center in Houston. After reviewing articles, only 33 of 965 articles considered, including 2,446 subjects, met the inclusion criteria. Antioxidants evaluated were: glutathione, melatonin, vitamin A, an antioxidant mixture, N-acetylcysteine, vitamin E, selenium, L-carnitine, Co-Q10 and ellagic acid. Nine studies reported no difference in toxicities between the 2 groups. Only 1 study (vitamin A) reported a significant increase in toxicity in the antioxidant group. This review provides some evidence that antioxidant supplementation during chemotherapy might reduce dose-limiting toxicities but it must be kept in mind that many of these so-called antioxidants have considerable prooxidant activity to which their salutary effects could also be attributed. Larger, well-designed studies of antioxidants impact on PDT, chemotherapy and tumoricidal radiation therapy are warranted. ¹⁸

However, until such data is available, considerations for utmost patient safety must prevail. The mechanisms of action of chemotherapeutic drugs and antioxidants are sufficiently understood to predict their resultant interactions and to suggest that considerable care should be exercised with respect to both clinical decisions and study interpretations. ¹⁹ Additionally, antioxidants have a wide variety of biochemical actions and are capable of interfering selectively with EMOD initiation, propagation and termination. EMODs have been studied for their positive effects in the prevention or cure of many cancers, cardiovascular disease, age-related diseases, and other disorders. ^20-23

Nonetheless, there seems to be agreement that the antioxidant N-acetylcysteine (NAC), a derivative of the naturally occurring amino acid cysteine, should be avoided by cancer patients because of studies showing interference with chemotherapeutic agents, such as cisplatin and doxorubicin. ^{24, 25} A 2005 report concluded that cancer patients should avoid antioxidant supplements while receiving chemotherapy or radiation treatment. ²⁶ Directed towards informing the public, a Wall Street Journal article argued that antioxidants could block the beneficial effects of standard cancer therapy. ²⁷

Those who recommend the use of antioxidants in cancer patients claim that antioxidants such as vitamin C, vitamin E, coenzyme Q10, glutathione, and selenium can reduce the toxicity of free radicals. ^28-31 Thus, EMOD-induced prooxidant apoptosis and the cancer conundrum leave us with unanswered questions regarding their interactions, auto-oxidation of antioxidants and the prooxidant character of many antioxidants. ³²

A 2007 article not only defends the use of antioxidants in cancer patients, it states that, “In 15 human studies, 3,738 patients who took non-prescription antioxidants and other nutrients actually had increased survival.” ³³ In contrast, a 2008 article in the Journal of the National Cancer Institute reviewed randomized trial data, which suggested that cancer patients should avoid the routine use of antioxidant supplements because they may potentially decrease the efficacy of cancer therapy by protecting the tumor and reducing survival. They looked at clinical trials investigating the impact of antioxidants on radiation therapy and found evidence suggesting that antioxidant supplementation reduced overall survival. ³⁴

Threshold levels of oxygen (O)

Cancer therapy can be aimed at the cell cycle, which consists of four phases, i.e., the G₁, S, G₂, and M phases. Based on their specificity, chemotherapy drugs can be classified as cell-specific agents (effective during certain cell cycle phases) and cell-cycle non-specific (effective during all phases of the cell cycle). Based on their specific characteristics and nature of treatment, chemotherapeutic agents can be classified as alkylating agents, anti-metabolites, anthracyclines, antitumor antibiotics, monoclonal antibodies, platinums, or plant alkaloids.

Many chemotherapeutic drugs have well-defined mechanisms of actions, including traditional alkylating agents and anthracycline antitumor antibiotics, which generate EMODs. Depending upon specifics of oxidation/reduction potentials, these EMODs are uniformly subject to transformation to altered compounds by antioxidants through the simple process of electron transfer.

Doxorubicin, arsenic-induced apoptosis and 2-Methoxyestradiol induced apoptosis

Antineoplastic therapy can be based on the cell cycle and/or it can be based on the involvement of electronically modified oxygen derivatives (EMODs), formerly called oxygen free radicals or reactive oxygen species. These prooxidant EMOD reactants induce apoptosis and appear to be essential as activators for ^{removing or killing cells that have accumulated mutations. 2-Methoxyestradiol induces apoptosis in Ewing sarcoma cells through mitochondrial hydrogen peroxide production. 42-44 Daunorubicin and doxorubicin can undergo redox cycling and produce EMODs, which can have a variety of effects, including damage to cell membranes and DNA-damage. 45}

Bleomycin and doxorubicin are two agents known to generate prooxidant oxygen ^{species. 46 In reactions involving Fe(II) and oxygen, an “activated” bleomycin species is formed that damages DNA through free radical intermediates. 47 Superoxide and hydrogen peroxide can also react with Fe(II) or Fe(III) bleomycin, respectively, to produce the activated form of the drug. DNA damage from bleomycin and ionizing radiation is similar in both induction and repair. 48}

Many chemotherapeutic drugs, such as tamoxifen, doxorubicin, mitomycin C, etoposide and cisplatin are superoxide (EMOD) generating agents and induce oxidative stress and apoptosis. ^{49, 50}

Reduction in EMOD levels generated by chemotherapeutic agents has the same effect as a reduction in dose. ⁵¹ NADPH-flavin reductase, cytochrome p450 reductase and mitochondrial NADH reductase can all reduce anthracyclines to a semiquinone radical. ⁵² This semiquinone radical can donate its free electron to molecular oxygen to generate the superoxide radical (O^• ₂). ⁵² Like hydrogen peroxide (H₂O₂), O^• ₂ can generate hydroxyl radicals (^•OH) upon interaction with metal ions. ⁵² This results in lipid peroxidation of plasma membranes, leading to a loss of mitochondrial inner membrane potential and consequent cytochrome c release and apoptosis. EMODs can also directly damage DNA through generation of strand breaks and oxidized nucleic bases such as guanine to 8-hydroxyguanine, giving rise to G-T transversions. ⁵²

However, as a caution, free radical generation by anthracyclines is thought to be responsible for the cardiotoxicity that puts some limits on their therapeutic use. ^{53, 54}

Ideal treatment should aim to selectively kill the cancer cells, without harming normal cells. Elegant regulation of prooxidant EMOD levels may be a means to this exalted goal.

Cancer ^{therapy seeks to utilize the sensitivity of transformed cells towards apoptotic signals, which allows the execution of apoptotic cell death. 55, 56 Contrary to Harman’s free radical theory in which EMODs are only deleterious, EMODs have been found to play a crucial beneficial role in intracellular apoptotic execution (cellular suicide). 57-61}

Glioma pathogenesis-related protein 1 (GLIPR1), a novel p53 ^{target gene, is down-regulated by methylation in prostate cancer and has p53-dependent and -independent proapoptotic properties in tumorous cells. Investigators reported that the expression of GLIPR1 is significantly reduced in human prostate tumor tissues compared with adjacent normal prostate tissues and in multiple human cancer cell lines and that overexpression of GLIPR1 in cancer cells leads to suppression of colony growth and induction of apoptosis. Mechanistic analysis indicated that GLIPR1 up-regulation increases EMOD production leading to apoptosis through activation of the c-Jun–NH₂ kinase (JNK) signaling cascade. These results identify GLIPR1 as a proapoptotic tumor suppressor acting through EMODs and the ROS-JNK pathway and support the therapeutic potential for this protein. 62}

Elesclomol (formerly STA-4783) is a novel small molecule undergoing clinical evaluation in a pivotal phase III melanoma trial (SYMMETRY). In a phase II randomized, double-blinded, controlled, multi-center trial in 81 patients with stage IV metastatic melanoma, treatment with elesclomol plus paclitaxel showed a statistically significant doubling of progression-free survival time compared with treatment with paclitaxel alone. Elesclomol induces apoptosis in cancer cells through the induction of oxidative stress (EMOD generation). Treatment of cancer cells in vitro with elesclomol resulted in the rapid generation of EMODs and the induction of a transcriptional gene profile characteristic of an oxidative stress response. Inhibition of oxidative stress by the antioxidant N-acetylcysteine (NAC) blocked the induction of gene transcription by elesclomol. In addition, N-acetylcysteine blocked drug-induced apoptosis, indicating that EMOD generation is the primary mechanism responsible for the proapoptotic activity of elesclomol. Excessive EMOD production and elevated levels of oxidative stress is believed by some to cause critical biochemical alterations that contribute to cancer cell growth. Thus, the induction of oxidative stress by elesclomol exploits this unique characteristic of cancer cells by increasing EMOD levels beyond a threshold that triggers cell death. ⁶³

The antitumor agent imexon activates oxidative stress and antioxidant gene expression, which is evidence for EMOD production. Results show that a predominant ^{biological effect of imexon is a change in redox state that can be detected in surrogate normal tissues as increased redox-sensitive transcription factor binding, EMOD generation and increased antioxidant gene expression. 64}

Investigators found that Chaetocin, a thiodioxopiperazine natural product previously ^{unreported to have anticancer effects, was found to have potent antimyeloma activity in IL-6–dependent and –independent myeloma cell lines in freshly collected sorted and unsorted patient CD138+ myeloma cells and in vivo. Chaetocin displays superior ex vivo antimyeloma activity and selectivity than does doxorubicin and dexamethasone, and dexamethasone- or doxorubicin-resistant myeloma cell lines are largely non–cross-resistant to chaetocin. Mechanistically, chaetocin is dramatically accumulated in cancer cells via a process inhibited by glutathione and requiring intact/unreduced disulfides for uptake. Its anticancer (antimyeloma) in vitro and in vivo activity appears to be mediated primarily via the imposition of oxidative stress (prooxidant EMODs) and consequent apoptosis induction. 65}

Investigators examined the cytotoxicity and mechanisms of ^{cell death of the broad-spectrum histone deacetylase (HDAC) inhibitor PCI-24781, alone and combined with bortezomib in Hodgkin lymphoma and non-Hodgkin lymphoma cell lines and primary lymphoproliferative (CLL/SLL) cells. PCI-24781 resulted in increased EMODs, oxidative stress and NF- B inhibition, leading to caspase-dependent apoptosis. They showed that bortezomib is synergistic with PCI-24781. This combination or PCI-24781 alone has potential therapeutic value in lymphoma. 66}

Zinc ^{is becoming increasingly important in regulating cancer cell growth and proliferation. Investigators showed that the anticancer agent motexafin gadolinium (MGd) disrupted zinc metabolism in A549 lung cancer cells, leading, in the presence of exogenous zinc, to cell death. They reported the effect of MGd and exogenous zinc on intracellular levels of free zinc, oxidative stress, proliferation, and cell death in exponential phase human B-cell lymphoma and other hematologic cell lines. They found that increased levels of oxidative stress, EMOD production and intracellular free zinc precede and correlate with cell cycle arrest and apoptosis. 67}

Many naturally occurring quinones can be isolated from biological ^{tissues. 68 Also, chemotherapeutic drugs (adriamycin, daunorubicin, and mitomycin), acetaminophen (Tylenol), and air pollutants (cigarette smoke and automobile exhaust) are common source of quinones. Some quinones have potential to markedly induce the generation of prooxidant EMODs and may serve as the molecular mechanism of quinone cytotoxicity. 68}

Hypoxic cancer cells are radio-resistant, which contributes dramatically to the inability of radiotherapy to control neoplastic growth and metastasis. Methods or therapies that provide increased prooxidant oxygen to cancer cells help radiation work more effectively by enabling more EMOD or free-radical formation. Radiation kills cancer cells by concentrating massive amounts of prooxidant free radicals directly into tumors.

Ionized radiation releases reactive ^{oxygen species, i.e., EMODs, from the water molecule. 69 Thus cancer patients who undergo radiation therapy may be exposed to significant quantities of reactive prooxidant species. This may produce overkill or generate dangerously high prooxidant levels in areas outside of the treatment target site. Radiotherapy aims to alter cellular homeostasis, modify signal transduction pathways, alter redox states and induce cellular apoptosis. Exposure to ionizing radiation produces prooxidant oxygen-derived free radicals including hydroxyl radicals (the most damaging), superoxide anion radicals, hydrogen peroxide and other oxidants. 70}

And finally, as reported on 2-04-09 in the journal Nature, Stanford researcher, Robert Cho, found that breast cancer stem cells make much higher levels of protective antioxidants than other cancer cells. Use of a drug to block the antioxidant, glutathione, caused the cancer stem cells to become far more vulnerable to radiation. Using cells from mice and human breast cancer, the antioxidant glutathione protected the cancer cells from being killed by radiation EMOD-induced apoptosis.

However, even though EMODs are effective in killing tumor cells, ^{they may threaten the integrity and survival of surrounding normal cells, which is dependent upon inherent tissue sensitivity and repair. Yet, the bottom line is that oxygen and its prooxidant EMOD agents are usually essential for effective radiation therapy and the induction of either apoptosis and/or necrosis.}

Hydrogen peroxide appears to have medical attributes but has received little support in modern medicine. Hydrogen peroxide (H₂O₂) is a moderate oxidant that induces apoptosis ^{of tumor cells in vitro. 71}

Even though the Baylor group’s research on cancer, heart disease, wound healing and infections in the 1960s on hydrogen peroxide was ground breaking, it has remained in obscurity. Still, it teaches the therapeutic potential of hydrogen peroxide in the treatment of cancer, wound healing, atherosclerosis, shock management and infectious diseases. Peroxide has been used widely in Europe and has had an impressive record of safety and effectiveness.

Many clinical and experimental applications of hydrogen peroxide have been demonstrated. In over 300 patients regional intra-arterial hydrogen peroxide potentiated the effect of radiation therapy for malignancy involving the head, neck, pelvis and retro-peritoneum. ⁷² Increased localization of radioactive isotopes in malignant tumors was achieved by regional and intra-arterial infusion of hydrogen peroxide. ^{73, 74} Oxygen enhanced environments were shown to be bactericidal for most clostridia species and inhibited alpha toxin release. Hyperbaric oxygen was shown to be a beneficial adjunct to therapy in Bacteroides fragilis, Fusobacterium infections and nonclostridial anaerobic soft tissue infections. ⁷⁵

Results with hyperbaric oxygen are similar to that obtained by the Baylor investigators using intra-arterial and intra-venous H₂O₂.

Hydrogen peroxide appears to have two distinct effects. It initially inhibits the caspases and delays apoptosis. Then, depending on the degree of the initial oxidative stress, the caspases are activated and the cells die by apoptosis, or they remain inactive and necrosis occurs. ^{76, 77} Some investigators believe that AIDS and cancer can be helped with hydrogen peroxide because of its induction of interferon-gamma production and its interactions which can produce a wide variety of oxygen derivatives. ⁷⁸

In a simple but rather elegant experiment, Davies showed that cellular division or cell death is EMOD concentration dependent, when utilizing the EMOD, H₂O₂. Cellular responses go from proliferation, to arrest, to apoptosis. ⁷⁷ Those opposing hydrogen peroxide use have accused it of acting as a “genotoxicant or epigenetic” ^{agent but although H₂O₂ can cause DNA damage, it is, at best, a very weak mutagen in mammalian cells. 79}

Vitamin C (ascorbate, ascorbic acid) has had a controversial history in the prevention of cancer. Based on the pioneering work of Dr. Hugh Riordan, there have been some significant subsequent developments. One clinical ^{case report by Drisko et al showed that vitamin C together with other oxidants, when added adjunctively to first-line chemotherapy, prevented recurrence in two ovarian cancer patients. 80 This high dose, intravenous vitamin C therapy was believed to operate through the generation of hydrogen peroxide. Ascorbate-mediated cell death was due to protein-dependent extracellular H₂O₂ generation (i.e., prooxidant EMOD generation). Ascorbate, an electron-donor in such reactions, ironically initiates prooxidant chemistry and H₂O₂ formation. It was concluded that ascorbate at pharmacologic concentrations in blood is a pro-drug for H₂O₂ delivery to tissues. 81, 82}

Vitamin ^{C acts as a cosubstrate for hydroxylase and oxygenase enzymes for the biosynthesis of procollagen, carnitine, and neurotransmitters. 83 These enzymes produce EMODs and ascorbate acts as a cosubstrate for them and thus, acts as a prooxidant. 84 Chen et al showed that at pharmacologic concentrations, ascorbate acts as a prooxidant, hydrogen peroxide generating agent, which exhibits selective cytotoxicity towards a wide variety of cancer cells in vitro and in vivo. 85, 86 Even though there is much to be discovered in the ascorbate and hydrogen peroxide system, this appears to be an area of great potential. 87}

Yet, in contrast, several vitamin C and iron co-supplementation ^{studies, both in animals and humans, indicate that vitamin C inhibits rather than promotes iron-dependent oxidative damage. 88}

Photodynamic therapy (PDT) holds considerable promise in treating cancer but current terminology leads to confusion.

First, we need a definition of terms:

Phototherapy - light, UV, etc., is shown on to the skin, such as treating hyperbilirubinemia in babies.

Photochemotherapy - uses a photosensitizer like, psoralin

Photodynamic therapy - uses a photosensitizer given to the patient to produce ¹O₂* (excited singlet oxygen).

Photo-oxidative therapy - also referred to as photo irradiative therapy, uses UV light shown on blood which is returned to the body.

Bio-oxidative therapy - aerobic exercise.

Autohemotherapy - ozone.

Photodynamic effect - a photon is absorbed by a photosensitizer and raises it to its lowest triplet excited state, it diffuses until it collides with O₂ and raises it to its lowest singlet state.

Photodynamic therapy requires a photosensitive compound and a light source (usually a laser) capable of energizing electrons to higher orbitals (excited states). These excited molecules in turn excite triplet oxygen to one of its singlet excited states in accordance with the amount of energy transferred to oxygen's outer orbital electrons.

The unique property of photosensitizers to selectively accumulate in malignant and dysplastic tissues is exploited in the treatment of malignancies. PDT can selectively destroy tumors with this simple concept. Compared to surgery and conventional thermal Yag and argon laser treatment, there is much less damage and disruption of the underlying and adjacent normal tissue structures with photodynamic therapy, since there is essentially no thermal damage to the tissues. Superficial treatments do not require sterile theater conditions and can be delivered in an outpatient setting. There is little post-treatment discomfort and the only significant side effect is residual photosensitivity.

Availability of ground state oxygen within the tumor can dramatically influence and limit direct tumor cell kill. ⁸⁹ Photodynamic therapy (PDT) is a novel therapeutic method for the treatment of malignant tumors, which utilizes prooxidant EMOD generation and in particular metastable singlet oxygen (¹O₂*). By combining PDT with hyperoxygenation, any underlying hypoxic condition is improved and the cell killing rate at various time points after PDT is dramatically enhanced. ^{90, 91}

In 1991, investigators described an apoptotic response to PDT. ⁹² Prooxidant species, especially singlet oxygen, produced by photosensitization or derived from cytotoxic agents, can activate apoptotic pathways. ⁹³ However, malignant cell types can exhibit an impaired ability to undergo apoptosis. PDT-mediated oxidative stress induces a transient increase in the downstream early response genes c-fos, c-jun, c-myc, and egr-1. ⁹⁴

The in vivo tumoricidal reaction after PDT is accompanied by a complex immune response. PDT is a highly effective means of generating tumor-sensitized immune cells that can be recovered from lymphoid sites distant to the treated tumor at protracted time intervals after PDT, which asserts their immune memory character. ^{95, 96} Vascular shutdown is clearly an important aspect of PDT. ⁹⁷

Clearly, when generated under carefully controlled conditions using exogenous sensitizers and light in the visible range (400 -700 nm), ¹O₂* can be exploited for therapeutic purposes, as in antineoplastic photodynamic therapy (PDT). In biological systems, singlet oxygen has a short lifetime of <0.04 s and has also been shown to have a short radius of action of <0.02 m. ⁹⁸

However, in a cell with quenchers or scavengers abounding, ¹O₂* lifetime can be <50 nsec with a diffusion distance <10 nm from its point of origin, which is less than 0.1% of the radius of an average eukaryotic cell. This short distance of reactivity can have clinical and therapeutic benefits and limit the target area or “zone of reactivity.”

Although controversial, it is important to remember that all antibodies apparently go through a singlet oxygen and ozone step. Antibodies can generate hydrogen peroxide (H₂O₂) from singlet molecular oxygen (¹O₂*). This process is catalytic, and investigators identified the electron source for a quasi-unlimited generation of H₂O₂. Antibodies produce up to 500 mole equivalents of H₂O₂ from ¹O₂*, without a reduction in rate. This work shows the enormous potential for H₂O₂ production by antibodies and their prooxidant mechanism of action. ^{99, 100}

Howes proposed a singlet oxygen generating system composed of physiological agents for the eradication of cancer, which did not have the limitations of conventional photodynamic therapy, radiation therapy or chemotherapeutic systems. In a pilot study at Tuft’s Medical School, athymic mice, which had received human squamous cell carcinoma, experienced a 22.7% tumor disappearance rate in the “high dose group” following injection with the Howes singlet oxygen producing system. ¹⁰¹

Even more encouraging results were seen, with an initial 80% disappearance rate, when basal cell skin cancers were similarly injected with this singlet oxygen delivery system. ¹⁰²

PDT generates similar products, in particular ¹O₂*, with similar chemical reactivity as the Howes Singlet Oxygen Delivery system.

Pioneering work in the 1970s by Howes and Steele on microsomal lipid peroxidation ¹⁰³ and aryl-hydroxylations ¹⁰⁴ demonstrated evidence for the generation and participation of electronic excitation states, namely singlet oxygen. This was the first demonstration of a functional generation of an electronic excitation state, exclusive of vision, in mammalian systems. Their proposal, that singlet oxygen is the identity of the long sought out “active oxygen” acting on the cytochrome P 450 microsomal mixed function oxidases, has more recently been supported by the work of Yasui et al in 2002. ¹⁰⁵

While studying widely divergent biological electronic excitation generating systems, such as the microsomal mixed function oxidases, the neutrophil respiratory burst ¹⁰⁶ and proline hydroxylation for collagen biosynthesis, one of the investigators (Howes) believed that these oxidative systems shared a point of convergence, expressed in the Howes Excytomer Pathway, involving superoxide anion and electronically excited singlet oxygen. ¹⁰⁷

Furthermore, Howes saw an additional commonality with generation of singlet oxygen produced by the steady-state physiological oxidative reagents containing an organic peroxide and the salt of hypohalous acid ¹⁰⁸

Subsequently, Howes reasoned that the peroxide/hypochlorite oxidative system may represent an ideal method of singlet oxygen delivery for effectively treating premalignant and malignant lesions, while simultaneously eliminating many of the drawbacks associated, not only with PDT, but with all other conventional methods of cancer therapy, including chemotherapy and irradiation. The peroxide/hypochlorite oxidative system has been shown to generate primarily singlet oxygen exclusively, as opposed to hydroperoxide/hypochlorite systems which have been shown to produce peroxyl and alkoxyl radicals. ¹⁰⁹

It has been reported that hyperbaric oxygen therapy, using pressures at or less than 2.5 ATA, do not significantly increase EMODs in the presence of normal antioxidant defenses. Hyperbaric oxygen increases the oxygen in tumor tissue, as well as EMOD and prooxidant levels, and appears to enhance the efficiency of PDT. ^{122, 123} Hyperoxygenation appears to provide effective ways for improving PDT efficiency by oxygenating both preexisting and treatment-induced cell hypoxia. ¹²⁴

Lest we forget, oxygen and prooxidant EMODs play a central protective role against pathogens, as well as a crucial role in cancer therapy.

Polymorphonuclear cells (PMNs) require oxygen to kill organism by producing prooxidant superoxide, hydrogen peroxide, singlet oxygen and other products via the respiratory burst. ¹²⁵ The PMN is protected by detoxifying free radicals with superoxide dismutase, catalase and glutathione. It has been shown in numerous studies that the degree of polymorphonuclear cell function in killing of bacteria is directly dependent on oxygen tension. ^{126, 127}

Scientists at The Ohio State University (OSU) have identified a way to predict very early in the treatment process the outcome of radiation and chemotherapy for cervical cancer patients and it is based on oxygen levels within the tumor. According to Jian Z. Wang, the oxygenation of a tumor is critical for the success of cancer treatment because the amount of oxygen in a cell is directly correlated with the ability of that cell to repair radiation damage. Wang stated that, “Inevitably, those well-oxygenated tumor cells die, tumors are less likely to return, and patient survival rates rise.” The research was described in the talk, “When the Oxygen Level Matters Mostly During Radiation Therapy of Cervical Cancer?” presented July 31, 2008 at the 50th annual meeting of the American Association of Physicists in Medicine.

Men with a low oxygen supply to their prostate tumor have a higher chance of the prostate cancer returning, as found by increasing prostate-specific antigen (PSA) levels following treatment, according to Benjamin Movsas, M.D., senior study author and chair of the Department of Radiation Oncology at Henry Ford Hospital. Moreover, recent studies suggest the same finding also appears to apply to patients treated with surgery. Movsas stated that “A tumor’s oxygen supply can significantly predict outcome following treatment, independent of tumor stage or Gleason score (a classification of the grade of prostate cancer).” ¹²⁸

In short, consideration of oxygen levels in cancer chemotherapy is crucial for successful eradication of neoplasia.

Various cancer chemopreventive agents can induce apoptosis in premalignant and malignant cells in vivo and/or in vitro, which serve as an anticancer mechanism. Many of these apoptogenic-inducing agents function as prooxidants in vitro.

Significant in vitro data exists showing that antioxidants can block EMOD-induced apoptosis for a wide variety of cancerous cell types, such as leukemia, lymphoma, retinoblastoma, myeloma, pheochromocytoma and human cancers of the breast, lung, pancreas, liver, colon, rectum and endometrium. This data can not be ignored when considering effective prooxidant cancer therapy. ¹²⁹

In 2001, Harvard Medical School investigators observed a dose dependent inhibition of MBT-2 cell (murine bladder cancer) growth after exposure to doxorubicin hydrochloride, which could be enhanced by hydrogen peroxide and inhibited by preincubation with alpha tocopherol. They concluded that hydrogen peroxide may be a relatively inexpensive, nontoxic method of augmenting the cytotoxicity of doxorubicin hydrochloride. ¹³⁰

To avoid the confusion with terms of the past, it is suggested that current scientific oxygen related therapies should be referred to as “prooxidant EMOD therapies.”