CancerReview_FINAL_multiL.qxp 23.02.2007 10:59 Seite 45 DR. MATTHIAS RATH’S CELLULAR HEALTH RESEARCH SERIES Clinical Nutrients in Cancer Therapy: A Scientific Review and Perspective A. Niedzwiecki and M. Rath (Editors) S. Netke, V. Ivanov, M.W. Roomi and T. Kalinovsky (Contributors) Dr. Rath Research Institute CancerReview_FINAL_multiL.qxp 23.02.2007 10:59 Seite 2 DR. MATTHIAS RATH’S CELLULAR HEALTH RESEARCH SERIES TABLE OF CONTENTS Introduction 5 The Physiological Targets of Effective Cancer Therapy 6 Individual Nutrients in Cancer Therapy 7 1. Vitamin C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7 1a.Possible Anti-Cancer Mechanisms of Vitamin C . . . . . . . . . . . . . . . . . . . . . . . . . . . .8 1b.Specific Concerns Regarding Vitamin C in Cancer . . . . . . . . . . . . . . . . . . . . . . . . .9 1c. Safety of High Intakes of Vitamin C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10 2. Green Tea Components (EGCG) and Green Tea Extract (GTE) . . . . . . . . . . . . . . . . . .11 3. N-Acetyl Cysteine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13 4. Selenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14 5. Arginine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15 Nutrient Combinations in Cancer Therapy 16 1. Scientific Rationale on the Novel Approach of Nutrient Synergy in Cancer Therapy 16 2. Nutrient Synergy: Vitamin C, Lysine, Proline, EGCG, Arginine, N-Acetyl Cysteine, Selenium, Copper and Manganese . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18 3. Other Nutrient Combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23 Nutrients as Adjuncts to Standard Cancer Therapy 24 1. Essential Nutrients Used with Chemotherapy Agents or Radiation Therapy . . . . . . .24 - Cisplatin with Selenium and Vitamin C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24 - Cisplatin with Vitamin C and Vitamin E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24 - Cisplatin, Tamoxifen, and Dicarbizine with Vitamin C, Vitamin E, Beta-Carotene and Retinoic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24 2 CancerReview_FINAL_multiL.qxp 23.02.2007 10:59 Seite 3 DR. MATTHIAS RATH’S CELLULAR HEALTH RESEARCH SERIES - Irradiation with Vitamin A and Beta-Carotene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24 - Doxorubicin and Vitamin E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25 - Doxorubicin and N-Acetyl Cysteine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25 - Cyclophosphamide, Methotrexate, and 5-Fluorouracil with Vitamin C . . . . . . . . . . .25 - Sulindac and Green Tea Extract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25 2. Combination of Multiple Antioxidants with Chemotherapy . . . . . . . . . . . . . . . . . . . .25 3. Reasons for Discrepancies in Obtaining Beneficial Therapeutic Effects of a Combination of Antioxidants with Standard Therapies . . . . . . . . . . . . . . . . . . . .27 4. Combinations of High Doses of Antioxidants Recommended by Various Research Groups for Use in Conjunction with Conventional Anti-Cancer Therapy . . . . . . . . . .28 Most Frequent Concerns of Oncologists Regarding Antioxidant Use in Cancer Therapy 31 1. Uncertainty About the Long-Term Effects of Combining Chemotherapy Drugs with Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31 2. Antioxidants and Cancer Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31 3. Antioxidant Interference with Chemotherapy Drugs and Irradiation (Mechanistic Aspects) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .33 4. Issues Related to the Use of Antioxidant Megadoses . . . . . . . . . . . . . . . . . . . . . . . . .35 Conclusions 38 References 39 About Matthias Rath, M.D. and His Mission 43 © 2005 Dr. Rath Research Institute. All Rights Reserved. First Printing: February 2005 3 CancerReview_FINAL_multiL.qxp 23.02.2007 10:59 Seite 4 CancerReview_FINAL_multiL.qxp 23.02.2007 10:59 Seite 5 DR. MATTHIAS RATH’S CELLULAR HEALTH RESEARCH SERIES The Clinical Effects of Cellular Nutrients in Cancer: A Scientific Review and Perspective Introduction Despite the extensive use of conventional therapies, cancer mortality has not decreased over the last few decades; on the contrary, it is increasing (Jemal, et al., 2002; Howe, et al., 2001). Standard cancer treatments generally involve a combination of surgery, multiple chemotherapeutic agents, and ionizing radiation. Apparently, these conventional approaches have not been successful in controlling cancer. Moreover, they are associated with the severe toxicity of chemotherapeutic agents, with the development of drug resistance by cancer cells, and with genotoxicity, giving rise to new cancers. This situation demands a revision of current approaches and the development of new strategies in the treat- ment of cancer aimed at increasing the efficacy of treatments, as well as reducing drug and radiation toxicity, and developing new therapies. In this regard, the use of micronutrients in therapeutic doses as an adjuvant or outright curative therapy in the treatment of cancer offers the most promise. In fact, approximately 80% of patients diagnosed with cancer seek alternative therapies, which include antioxidants and other essential nutri- ents. However, some representatives of mainstream medicine have attacked supplements of vitamins and other essential nutrients as potentially harmful. These attacks are unjustified and are being published despite scientific evidence showing that cancer patients who use supplements do benefit from them. In the search for effective solutions to cancer, the work of Rath, et al. (1992) provides a new perspective in the therapeutic use of essential nutrients, such as vitamin C and lysine, in the control of cancer growth and metasta- sis. Further research in this direction at the Dr. Rath Research Institute of Cellular Medicine under the direction of Dr. Aleksandra Niedzwiecki has led to the development of a particularly effective natural approach to the control of cancer based on nutrient synergy. In this documentation, we summarize the available evidence that this nutrient synergy is the most effective way currently available to control the critical processes of cancer, including metastasis, angiogenesis, cell prolifera- tion and apoptosis. We also review the available clinical information about the use of individual nutrients in can- cer therapy and provide an encouraging perspective on the application of nutrient synergy in clinical medicine. 5 CancerReview_FINAL_multiL.qxp 23.02.2007 10:59 Seite 6 DR. MATTHIAS RATH’S CELLULAR HEALTH RESEARCH SERIES The Physiological Targets of Effective Cancer Therapy Effective cancer therapy should achieve one or more of the following objectives (Figure 1): A. Prevention of the metastasis (tissue invasion) of cancer cells B. Prevention of the replication of cancer cells C. Prevention of angiogenesis (new blood vessel formation) in tumors D. Stimulation of apoptosis (programmed cell death) in cancer cells and destruction of cancer cells The most critical aspect of cancer in terms of patient survival is stopping cancer metastasis. This process, as well as many other aspects of neoplasia, are closely connected to the interaction between cancer cells and the extra- cellular matrix (ECM). Various nutrients primarily affect the properties of ECM; among them are vitamin C, as well as the amino acids lysine and proline, which play the most important role. The literature is also replete with clear evidence that other nutrients can also modify or regulate various stages in cancer promotion and the progression of cancer cells. Therefore, we critically evaluated the published evidence regarding the efficacy of various nutri- ents important in achieving one or more of the above objectives of effective cancer therapy. Cell Viability Cell Replication THERAPEUTIC TARGETS: Angiogenesis (new blood vessel growth) Metastasis Tumor Growth Prevention Induction of Apoptosis (cell death) Tumor Encapsulation EXPECTED RESULTS: (curbs metastasis) Inhibition of Angiogenesis Figure 1 6 CancerReview_FINAL_multiL.qxp 23.02.2007 10:59 Seite 7 DR. MATTHIAS RATH’S CELLULAR HEALTH RESEARCH SERIES Individual Nutrients in Cancer Therapy 1. Vitamin C Vitamin C (ascorbate) has been the most researched and applied nutrient in cancer. Since the time Cameron reported that vitamin C had beneficial effects on cancer patients (Cameron and Campbell, 1974), several studies have been published regarding the therapeutic potential of this nutrient (Meadows, et al., 1991; Tsao, 1991; Liu, et al., 2000; Alcain, et al.,1994). In 1978, Cameron and Pauling reported the results of a clinical study in Scotland in which 100 terminal cancer patients were given 10 g of supplemental sodium ascorbate. The survival time of these patients was compared with a control group of 1,000 patients that did not receive any ascorbate. The results showed that patients in the ascorbate-treated group had an increased average survival time of 321 days as compared to the matched control. Twenty-two patients in the ascorbate-treated group of 100 patients survived for more than one year (22%) versus only four out of 1,000 in the control group (0.4%). This study, based on the hospital records of the cancer patients, was retrospective, not prospective. As a result, it was criticized for not being free from bias with respect to patient selection (Moertel, et al., 1985). Moertel and his group conducted prospective double-blind studies using 10 g of vitamin C in patients that had not received prior chemotherapy. All the selected patients were in the advanced stage of large bowel cancer, and were considered otherwise untreatable; however, the study could not establish any treatment benefits. Cameron and Campbell (1991) also conducted prospective studies in cancer patients. In one study, patients in the vitamin C group received 10 g of sodium ascorbate daily. Many patients in the vitamin C group were admin- istered the designated dose of ascorbate intravenously for the first 10 days. The survival time for 50% of the patients in the vitamin C group was 343 days. For the control group, the mean survival time was 180 days. The investigators stated that these results indicated that patients receiving supplemental vitamin C lived longer than those who did not. They also found a positive correlation between the plasma vitamin C levels of patients and their survival time. The inverse relationship between plasma vitamin C levels and cancer-related mortality was also later confirmed by Khaw, et al. (2001). While these results were encouraging, they were not compellling enough to be accepted by mainstream clinical medicine. The diverging results among various trials are intriguing. A review of some in vitro studies will be helpful in the interpretation of these differences. In an in vitro study, vitamin C is added to cancer cells cultured in media. Cell growth is measured by counting the number of cancer cells after pre-designated incubation periods. The vitamin C levels effective in inhibiting the proliferation of cancer cells in various studies ranged between 400 µM and 1 mM (Leung, et al., 1993; Riordan, et al., 1995; Koh, et al., 1998; Netke, et al., 2003; Harakeh, et al., 2004). Can these vitamin C levels be obtained in the human body? Vitamin C blood concentration depends on its rate of absorption from the digestive tract and its rate of elimination by the kidneys. When 1,000 mg of ascorbic 7 CancerReview_FINAL_multiL.qxp 23.02.2007 10:59 Seite 8 DR. MATTHIAS RATH’S CELLULAR HEALTH RESEARCH SERIES acid was given orally daily, the steady-state plasma level of ascorbic acid was about 80 µM (Levine, et al., 1996). The studies also indicated that with higher intake, such as 2,500 mg daily, the plasma levels of ascorbic acid could reach the 100 µM range. It can thus be seen that reaching the required levels of ascorbic acid in the blood sufficient for inhibiting cell proliferation is difficult to achieve by oral administration. The question then becomes whether the desired plasma levels of ascorbate can be achieved by intravenous injections without any adverse effects to patients. In the studies reported by Riordan, et al. (1995), patients were given ascorbic acid intravenously. The patients were first screened for any adverse reactions to ascorbic acid by receiving smaller doses intravenously. They were then administered 115 g of ascorbic acid dissolved in one liter of Ringer’s Lactate by drip over an eight-hour period. Each patient was given 39 such infusions over a period of 13 weeks. Between infusions, patients received ascorbic acid orally to bowel tolerance (approximately 10 g daily). Plasma ascorbic levels as high as approximately 10 mM (180 mg/dl) were obtained in these studies, and there was no progression of disease during the period of administration of vitamin C. Such high ascorbate con- centrations are still within physiologically recognized ranges, since it has been reported that its intracellular con- centrations in lymphocytes under different oral supplementation are approximately 4 mM (Levine, et al., 2001) and in activated lymphocytes, ascorbate levels can reach 10 mM (Victor, et al., 2001). It is thus clear that high plasma levels of vitamin C are necessary to achieve beneficial results in cancer patients, and these levels can be achieved by intravenous injection of vitamin C. In the studies of Moertel, et al. (1985), vitamin C was given orally, not intravenously, as was done in the studies reported by Cameron and Campbell (1995). The difference in the mode of administration of vitamin C might explain the difference in the outcome of the studies. Parenteral administration of ascorbic acid is slowly finding acceptance in the conventional medical community. Drisko, et al. (2003), of the Division of Gynecologic Oncology at the University of Kansas Medical Center (USA), used 60 g of ascorbate administered parenterally twice a week, in addition to megadoses of antioxidants given orally, in two ovarian cancer patients. This treat- ment achieved satisfactory results, and the patients had remained cancer-free for more than three years by the time the report had been published. Again, these studies were not able to provide compelling results on the therapeutic value of vitamin C in cancer to be accepted by mainstream medicine. 1a. Possible Anti-Cancer Mechanisms of Vitamin C It has been generally assumed that vitamin C functions as an anti-cancer agent because of its antioxidant activi- ty, that is, by quenching the reactive oxygen species (ROS). Now it is known that vitamin C exercises its effects in several other ways. The studies of Maramag, et al. (1997) with prostate cancer cells indicate that vitamin C inhibits cell division and growth by the production of hydrogen peroxide. Singlet oxygen scavengers, such as sodium azide and hydro- quinone, and hydroxyl radical scavengers, such as d-mannitol and dl-alpha-tocopherol, did not counteract the effects of ascorbic acid on thymidine incorporation, suggesting that vitamin C-induced changes were not relat- ed to ROS. 8 CancerReview_FINAL_multiL.qxp 23.02.2007 10:59 Seite 9 DR. MATTHIAS RATH’S CELLULAR HEALTH RESEARCH SERIES Ultra-structural and cell surface studies on squamous cell carcinoma and basal cell carcinoma induced by 3- methylcholanthrene have revealed that ascorbic acid significantly affected cell growth and differentiation. Multiple effects, such as cytolysis, cell membrane disruption, mitochondrial alterations, nuclear and nucleolar reduction and increased phagolysosome formation, were observed in cancer cells following vitamin C adminis- tration (Lupulescu, 1992). Vitamin C has been shown to positively modulate several genes, such as fra-1 glutathione S-transferase pi (GSTpi) and Mut L homologue-1 (MLH-1), in human cells. It was demonstrated that MLH-1, as well as its down- stream target p73, can be positively modulated by this vitamin. The upregulation of two relevant mRNAs was observed after only two hours of exposure to ascorbate, and continued to increase during 16 hours of treat- ment. The modulation of MLH-1 and p73 gene expression improved cellular susceptibility to apoptosis trig- gered by the DNA-damaging agent Cisplatin, as well as p73. This activity was independent of p53 (Catani, et al., 2002). Our studies in collaboration with Dr. Harakeh and others (Harakeh, et al., in preparation) indicate that vitamin C can exert apoptotic effects on several leukemia cell lines, including HTLV-1 infected leukemia cells, by upregu- lating the expression of pro-apoptotic p53, p21, and Bax and downregulating the protein Bcl-2a expression. Vitamin C plays a critical role in the production and structure of collagen fibers and largely defines the compo- sition of ECM. Consequently, vitamin C can increase ECM strength, creating an encapsulating effect that can hinder cancer cell spread (Rath and Pauling, 1992; Roomi, et al., 2003). 1b. Specific Concerns Regarding Vitamin C in Cancer - Vitamin C Acting as a Pro-oxidant in Certain Circumstances Various in vitro studies have indicated that the interaction between vitamin C and free catalytically active metal ions could contribute to oxidative damage by the production of hydroxyl and alloxyl radicals. In essence, this means that ascorbic acid can act as a pro-oxidant instead of an antioxidant in the body. Carr and Frei (1999) reviewed several studies investigating the effects of vitamin C incubated in the presence and absence of metal ions on oxidative damage to DNA, lipids, and proteins. These studies provided com- pelling evidence for the antioxidant protection of lipids by vitamin C in biological fluids and in animals and humans, both with and without iron supplementation. Although the data on protein oxidation in humans was sparse and inconclusive, the available data in animals consistently confirmed the antioxidant role of vitamin C. The review, which evaluates several relevant studies, does not support the statement that vitamin C acts as a pro-oxidant in the body. 9 CancerReview_FINAL_multiL.qxp 23.02.2007 10:59 Seite 10 DR. MATTHIAS RATH’S CELLULAR HEALTH RESEARCH SERIES - Vitamin C and the Production of Genotoxins Fear has been spread that higher intakes of vitamin C can cause the production of genotoxins. This apprehen- sion stems from the studies of Lee, et al. (2001). These researchers reported that intake of 200 mg of vitamin C per day induced the decomposition of lipid hydroperoxides to endogenous genotoxins. These conclusions were reached based on in vitro studies in which very high levels of lipid hydroperoxides (400 micromol/liter) were used. Such high levels are not physiologically relevant. The physiological blood levels of hydroperoxides are an order of magnitude lower, ranging only between 10-500 nmol/liter. The probability of obtaining even these lev- els of hydroperoxides in vivo is low because high intake of vitamin C augments glutathione in human lympho- cytes, which inhibits lipid peroxidation (Lenton, et al., 2003). Levine, et al. (2001) also reported that higher levels of vitamin C intake did not produce higher levels of lipid peroxides. - Vitamin C and Mutagenic Effects Podmore, et al. (1998) claimed that dietary vitamin C intake of 500 mg/day may exert pro-oxidant and muta- genic effects in humans based on the increase in number of modified DNA bases in lymphocytes, in particular 8-oxoadenine. These studies indicated, at the same time, a significant decrease in 8-oxoguanine concentrations. 8-oxoguanine is an important mutagenic lesion in DNA. Any decrease in the concentration of 8-oxoguanine indicates that vitamin C can protect DNA from mutagenic alterations. The study findings of Podmore’s group have to be taken with reservations because the method of estimation of the oxo-compounds used was not reliable. It is known that these compounds can be formed during the process- ing of samples. 1c. Safety of High Intakes of Vitamin C - Kidney Stone Formation Concerns have been raised about the possibility that higher intakes of vitamin C can lead to the formation of renal calcium oxalate stones. A thorough search conducted by Goodwin and Tangum (1998) of the medical liter- ature found no reliable articles supporting this concern. On the contrary, three case-controlled studies did not show a clear association between ascorbate intake and excretion and stone formation (Cowley, et al., 1987; Power, et al., 1984; Felstrom, et al., 1989). The positive association between vitamin C and kidney stones reported by some workers may be because older assays for urinary oxalates allowed the conversion of urinary ascorbic acid to oxalates during the storage and processing of the samples. 10