Integrative Regulatory Therapy Research

Chapter 5: Oxidizing Cancer to Death

Oxidant Stress – and How Cells Cope with It

It is common knowledge that "free radicals" and "oxidants" are important mediators of disease – but what are these compounds? In most stable molecules, electrons occur in pairs. Molecules that contain unpaired electrons tend to be unstable and are known as "radicals" or "free radicals." Because they are unstable, they have a tendency to extract another electron from another molecule, or to donate their unpaired electron to another molecule. In either case, the attacked molecule is usually converted to a radical in the process. In living cells, this can give rise to a chain reaction of molecular damage.

The chief way in which free radicals arise in a body's cells is by donation of an electron to molecular oxygen, generating a compound known as superoxide. This reaction can be catalyzed by several natural enzymatic reactions in cells. Superoxide can then, via spontaneous or enzyme-catalyzed reactions, give rise to other reactive compounds such as hydrogen peroxide or peroxynitrite. These compounds are not themselves free radicals, but they often give rise to free radicals, and they also can act to alter the structure and function of proteins by "oxidizing" them. Unsaturated fatty acids in membranes are also prone to oxidation by free radicals.

Because unabated damage by free radicals and oxidants can cause major and often adverse changes in the structures of cellular proteins and fats, living organisms have developed antioxidant mechanisms. Certain enzymes, as well as electron-donor molecules known as antioxidants, can "fix" free radicals by electron donation. This can work in other ways to prevent or undo the damage to biological molecule wrought by oxidant reactions. Examples include enzymes such as superoxide dismutase, catalase, glutathione peroxidase, and thioreductase, and antioxidant molecules such as glutathione and vitamins C and E. In normal healthy cellular metabolism, the production of oxidants is balanced by the action of antioxidant mechanisms that prevent free radical damage from getting out of hand and overwhelming the cell. But sometimes, either because of excess production of radicals and oxidants, or because of inadequately protective antioxidant mechanisms, free radical damage can get the upper hand - a condition known as "oxidant stress." Oxidant stress is not always bad. In fact, induction of oxidant stress is one way in which some cytotoxic drugs kill cancer cells. On the other hand, as we shall see, a constant moderate level of oxidant stress in some cancers renders them more aggressive and harder to kill.

A high proportion of cancers have low activity of the enzyme catalase, which degrades the oxidant chemical hydrogen peroxide (1-3). This adaptation may be beneficial to the cancer. Although oxidant chemicals can be toxic to cells, moderate increases in oxidant stress aid the growth and survival of many cancers (4-7). However, low catalase makes cancers potentially vulnerable to attack with hydrogen peroxide. Recently, researchers at the National Institutes of Health have discovered that high concentrations of vitamin C (ascorbate) can react spontaneously with molecular oxygen within tumors to generate large amounts of hydrogen peroxide, which can be lethal to tumor cells whose catalase activity is low (8,9). Such large concentrations can only be achieved by high dose intravenous infusions of vitamin C. Oral administration is ineffective in this regard (10). These findings rationalize several previous case reports of objective tumor regression in cancer patients treated repeatedly with high-dose intravenous vitamin C (11-13). Vitamin C is not toxic to normal healthy tissues because they have ample amounts of catalase activity. The current protocol insures that blood and tissue levels of vitamin C will remain high, with millimolar levels close to those of blood sugar for at least 4 hours.

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Vitamin K3 as an Adjuvant

The ability of ascorbate (vitamin C) to generate hydrogen peroxide in tumors apparently hinges on the presence of unknown catalysts that can transfer electrons from ascorbate to oxygen molecules, generating the unstable compound superoxide (8,9). The latter is rapidly converted to hydrogen peroxide, which can move into cancer cells, and mediates the tumor cell death achieved with successful ascorbate therapy. Dr. Mark Levine, whose research encouraged us to develop the IRT-C protocol, speculates that extracellular protein-bound iron serves as this catalyst (9). It is conceivable that the availability of this catalyst might vary from tissue to tissue and person to person, depending on nutritional status or genetics. Furthermore, there is no reason to assume that levels of this catalyst are sufficient to permit an optimally intense generation of hydrogen peroxide in tissues.

However, it is not necessary to rely on unknown endogenous catalysts for this purpose. Certain small soluble organic molecules can perform the same catalytic function, expediting the transfer of electrons from ascorbate to oxygen. In particular, menadione, also known as vitamin K3, has this capacity (14). Menadione may be particularly appropriate for this purpose, as it has long been in clinical use as a source of vitamin K activity (15).

Moreover, there is substantial research literature demonstrating that joint incubation with sodium ascorbate and menadione is often selectively toxic to cancer cells. This phenomenon has been demonstrated with a wide range of human and rodent cancer (16-20). In striking parallel to the studies which report that high concentrations of ascorbate alone can exert such toxicity, it has been shown that concurrent incubation with the enzyme catalase – which destroys hydrogen peroxide – markedly alleviates this toxicity, demonstrating that hydrogen peroxide mediates this cancer-killing effect. Furthermore, cancer cells which express relatively low levels of catalase are more susceptible to this toxicity than cancer cells with higher levels of this activity. The selective susceptibility of cancer cells, as contrasted to normal cells, reflects the tendency of cancers to have lower levels of catalase and other enzymes which dispose of hydrogen peroxide (14,21). This, in turn, may reflect the fact that low concentrations of hydrogen peroxide promote cellular proliferation and survival in many cancers. In other words, low catalase activity, by enabling cancers to sustain modest concentrations of hydrogen peroxide, may make some cancers more aggressive and viable (21) – that is, until they are assaulted with high concentrations of ascorbate.

Researchers at the Catholic University of Louvain, Belgium, have played a pioneering role in demonstrating the potential utility of ascorbate/menadione in cancer therapy. In particular, they have shown that injection, or even oral administration of these agents, can retard cancer growth and metastasis in tumor-bearing rodents (14,22,23). They report that this therapy is well tolerated, without any evident damage to healthy tissues, and they recommend that this strategy should be assessed in clinical trials. They also demonstrate that ascorbate/menadione can interact synergistically with certain cytotoxic chemotherapy drugs in killing cancer cells, presumably because a concurrent increase in oxidant stress can make these drugs more lethal (24). This observation has been independently confirmed (25). Indeed, there are reports that menadione alone can potentiate the cytotoxicity of certain chemotherapy agents, presumably because, in sufficiently high concentrations, intracellular menadione can generate oxidant stress by transferring electrons from intracellular molecules to oxygen (26,27).

Since injectible vitamin K3 has long been clinically available in Mexico, we now administer this vitamin just prior to the vitamin C infusions. It is our hope and expectation that inclusion of menadione in the ascorbate infusions will markedly potentiate generation of hydrogen peroxide in tumors, enabling a more substantial cell kill in those cancers that are sufficiently low in catalase activity.

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Tumor Oxygenation – Ozone and Perftec

However, this strategy can only work well in tumors that have adequate levels of oxygen, as ascorbate reacts with oxygen to produce the hydrogen peroxide. Portions of many tumors tend to be low in oxygen (hypoxic), as the blood flow through tumors is often sluggish compared to that which supplies normal tissues. This evidently could compromise the anti-tumor efficacy of vitamin C therapy. To overcome this problem, Oasis of Hope Hospital employs several complementary techniques that can boost the oxygen content of tumors. Ozone autohemotherapy (O3-AHT) alters the properties of blood so that it is less viscous, its cellular elements are more flexible, and its oxygenated red blood cells surrender oxygen to tissues more readily. This is shown as a rightward shift of dissociation curve. It also promotes vasodilation by stimulating nitric oxide release by the endothelial lining of small arteries (28). The net result is more oxygen delivery to the tumor (29,30). Many tumors contain regions in which oxygen content is low, and hypoxic tumor cells typically are harder to kill with radiotherapy or chemotherapy. Thus, protocols which can boost tumor oxygen levels have potential as adjuvant measures in cancer therapy. Recently, researchers at the Canary Islands Institute for Cancer Research recruited 18 cancer patients and used special needle probes to measure the oxygen content of their tumors before and after 3 sessions of O3-AHT. They were in fact able to establish that there were fewer hypoxic tumor regions following O3-AHT (29).

At Oasis of Hope, O3-AHT is used not only in conjunction with chemotherapy, but also with high-dose intravenous sodium ascorbate therapy for IRT-C. This strategy involves drawing 200 ml of a patient’s blood, treating it with a mixture of ozone and oxygen, and re-infusing it. This procedure is typically repeated several times weekly. It is important to stress that Oasis of Hope employs an O3-AHT protocol that has been widely utilized in Europe for decades with an excellent safety record. The safety of this strategy reflects the fact that no ozone is infused into the body. Ozone is very unstable, and for practical purposes is completely dissipated before the ozone-treated blood is returned to the body. Thus, the body is exposed to ozone oxidation products, rather than ozone itself. Exposure of blood to ozone in clinically appropriate amounts does not cause lysis of red blood cells, or compromise the functional viability of white cells. No evident side effects are noted in patients receiving O3-AHT.

Oasis of Hope also has a novel perfluorochemical emulsion known as Perftec that is an oxygen carrier. When infused into a patient, it greatly boosts the total oxygen carrying capacity of blood (31). After Perftec infusion, patients are asked to breathe air that is enriched in oxygen content, so that the circulating Perftec is loaded with optimal amounts of oxygen. The combination of ozone autohemotherapy and Perftec infusion can be expected to improve oxygen availability in hypoxic regions of tumors. This in turn should boost the ability of intravenous ascorbate and vitamin K to generate hydrogen peroxide in tumors.

Concurrent Chemotherapy

Many patients will also receive cancer chemotherapy on the same day that they receive intravenous vitamin C. There are reasons to believe that the oxidant stress induced by the vitamin C in the tumor, as well as the improved tumor oxygenation made possible by ozone therapy and Perftec, will often increase the ability of the administered chemotherapy drugs to kill cancer cells (32-38). The Oasis of Hope Vitamin C Protocol has been designed to exploit these complementary interactions so that destruction of cancer cells can be maximized without increasing the toxic risk to healthy tissues.

Although many patients will be treated with chemotherapy, some will not. In some cases, the type of cancer is known to be resistant to available chemotherapy drugs. In other cases, patients elect to forego chemotherapy for personal reasons. For these patients, it is hoped that a vitamin C & K3/tumor oxygenation regimen will be sufficient to achieve worthwhile destruction of the tumor.

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Other Adjuvant Measures

We are currently employing additional adjuvant measures that, in at least some tumors, are likely to potentiate the killing of tumor cells achieved through our vitamin C & K3/chemotherapy regimen. The natural compound salicylate is derived from white willow bark, which has been for centuries as an anti-inflammatory therapy. It can enhance the sensitivity of many tumors to chemotherapy and hydrogen peroxide by inhibiting the activity of "NF-kappaB" (39,40). This factor is activated in a high proportion of advanced cancers, and works in multiple ways to render these cancers less sensitive to chemotherapy and oxidant stress (41,42). Although the drug aspirin is a chemical relative of salicylate, the latter does not have the potential to cause bleeding ulcers or kidney failure as aspirin does (43,44). The main common side effect of salicylic acid therapy is a reversible impairment of ear function associated with a mild loss of hearing acuity and/or "ringing in the ears" (tinnitus). These problems go away after salicylate is discontinued (45). At Oasis of Hope Hospital, the form of salicylate we use is known as "salsalate" (Disalcid). This is less likely to cause stomach upset than is sodium salicylate (46).

Prior to receiving vitamin K3 and vitamin C (and possibly chemotherapy), patients are also supplemented with the nutrient selenium and the herb silymarin, which is a source of the natural anti-inflammatory compound silibinin. Like salicylate, these agents have potential for sensitizing tumors to destruction by chemotherapy or oxidant stress. Silymarin's activity in this regard may be similar to salicylate's. It suppresses activation of NF-kappaB (47,48). Recent studies show that high doses of organic selenium can make cancer cells more sensitive to many types of chemotherapeutic drugs (49). There are reasons to believe that selenium may also make hydrogen peroxide more lethal to tumors. We now administer selenium in a form known as methylselenocysteine (MSC), which is a natural organic form found in certain foods. MSC is the preferable form for this application because it is rapidly metabolized to release the organic selenium metabolites useful in cancer therapy.

We also will be exploring the use of activated vitamin D (calcitriol) as a chemosensitizing agent in cancer therapy. Calcitriol appears to be quite safe if administered in only one or two doses a week, and if the concurrent diet is relatively low in calcium (50). Calcitriol has been shown to boost the sensitivity of many cancers to chemotherapy drugs or hydrogen peroxide (51,52).

During their stay at Oasis of Hope Hospital, patients will also be supplemented with various nutrients such as fish oil, green tea polyphenols, and melatonin. The purpose is to slow tumor growth by blocking new blood vessel formation (angiogenesis) or boosting the body's immune capacities. Supplementation with these nutrients will continue after patients return home between hospital therapy sessions. This "after-therapy" can be crucial for improving chances of a cure or at least achieving a worthwhile prolongation of high-quality life.

Don’t Be Confused

Controlled clinical studies that show that "vitamin C therapy" does not work in cancer only assessed oral vitamin C therapy (11). As noted, oral vitamin C can achieve only very modest increases in blood ascorbate levels. Intravenous vitamin C therapy has far greater credibility, and indeed is currently being formally evaluated in clinical trials at the U.S. National Institutes of Health.

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