Journal of the American College of Nutrition, Vol. 20, No. 90005, 450S-463S (2001)
Published by the American College of Nutrition
Scientific Rationale for Using High-Dose Multiple Micronutrients as an Adjunct to Standard and Experimental Cancer Therapies
Kedar N. Prasad, PhD,
William C. Cole, PhD,
Bipin Kumar, MD and
K. Che Prasad
Center for Vitamins and Cancer Research, Department of Radiology, School of Medicine, University of Colorado Health Sciences Center (K.N.P., W.C.C., B.K.), Denver, Colorado
Department of Pathology, University of California (K.C.P.), San Francisco, California
Address reprint requests to: Kedar N. Prasad, PhD, UCHSC, Dept. of Radiology, Box C278, 4200 E. 9th Avenue, Denver, CO 80262. E-mail: Kedar.prasad{at}UCHSC.edu
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ABSTRACT
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We have hypothesized that high-dose multiple micronutrients, including antioxidants, as an adjunct to standard (radiation therapy and chemotherapy) or experimental therapy (hyperthermia and immunotherapy), may improve the efficacy of cancer therapy by increasing tumor response and decreasing toxicity. Several in vitro studies and some in vivo investigations support this hypothesis. A second hypothesis is that antioxidants may interfere with the efficacy of radiation therapy and chemotherapy. This hypothesis is based on the concept that antioxidants will destroy free radicals that are generated during therapy, thereby protecting cancer cells against death. None of the published data on the effect of antioxidants in combination with radiation or chemotherapeutic agents on tumor cells supports the second hypothesis. Scientific rationale in support of a micronutrient protocol to be used as an adjunct to standard or experimental cancer therapy is presented.
Key words: antioxidants, cancer therapy, hyperthermia, sodium butyrate, cAMP
Key teaching points:
• Normal cells and tumor cells differ in their responses to antioxidants.
• Low-dose and high-dose antioxidants differ in their effect on tumor cells.
• Some actions of antioxidants on tumor cells are unrelated to scavenging of free radicals.
• High-dose antioxidants enhance the growth-inhibitory effects of irradiation, chemotherapeutic agents and hyperthermia on tumor cells, but they may or may not protect normal cells against such damage.
• Antioxidants have profound effects on the regulation of gene expression in tumor cells.
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INTRODUCTION
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The role of micronutrient supplements, diet and lifestyle modifications in the prevention and treatment of human cancer is being investigated by both basic and clinical scientists [1–3]. Two opposing hypotheses regarding the use of antioxidants as an adjunct to standard cancer therapy have recently been proposed. We have suggested that high-dose multiple antioxidant supplements before and during standard or experimental cancer therapy may improve treatment efficacy by increasing tumor response and decreasing toxicity [1]. An alternative hypothesis is that antioxidant supplements should not be used while treating cancer patients with standard therapy because they would protect both normal and cancer cells against free radicals that are produced by most of the anticancer agents [4]. These two conflicting hypotheses can be resolved if the following scientific principles are followed: (a) the results of the effects of low-dose (physiological range) antioxidants on cells are not extrapolated to those obtained with high-dose (pharmacologic, but non-toxic dose range) antioxidants; (b) data on the effects of a single antioxidant on cells are not extrapolated to those obtained with multiple antioxidants; (c) results of the effects of antioxidants on cancer cells are not extrapolated to those observed on normal cells; (d) data obtained on the effects of short treatment duration with antioxidants are not extrapolated to those obtained after long treatment duration; (e) all biological observations on the effects of antioxidants on cells are not related to their action of scavenging free radicals; and (f) all antioxidants do not produce similar effects on cells.
The purpose of this review is to analyze each of the above scientific principles to demonstrate that current opinions opposing the use of antioxidants as an adjunct to standard cancer therapy have no scientific basis, and that micronutrient supplementation, including antioxidants, under appropriate conditions may improve the efficacy of the current management of human tumors.
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EFFICACY OF CANCER THERAPY
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Standard Therapy
The efficacy of standard therapy involving a combination of surgery (when feasible), multiple chemotherapeutic agents and ionizing radiation has reached a plateau for most solid tumors. In some cancers, where standard therapy has produced increased cure rates, there exists the possibility of developing second cancers as a result of treatment. In addition, standard therapy also produces acute toxicity during treatment. This toxicity can be severe enough to cause discontinuation of certain therapeutic agents. Therefore, agents which could reduce the toxicity of standard therapy on normal cells, and/or which could increase the response of tumor cells to standard therapy, may markedly improve the current management of human cancer.
Experimental Therapy
Among experimental cancer therapeutic approaches, hyperthermia, immunotherapy, biological response modifiers, and gene therapy are being used to treat human cancers on a limited scale. The clinical results of each of these modalities have been variable and unimpressive.
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EFFECT OF ANTIOXIDANTS ON CANCER CELLS
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Low-Dose vs. High-Dose
Antioxidants such as retinoic acid (and its derivatives), vitamin E (
-tocopheryl succinate and the aqueous form of vitamin E), vitamin C and carotenoids (primarily ß-carotene and polar carotenoids), when used individually at high-doses, induce cell differentiation, growth-inhibition and apoptosis in rodent and human cancer cells in vitro and in vivo [1–3]. An example of -tocopheryl succinate (-TS)-induced differentiation of melanoma cells in culture is presented in Fig. 1. A summary of the clinical efficacy of retinoids is described in Table 1. Several mechanisms of action of high-dose antioxidants on cancer cells in vitro have been proposed, some of which are listed below. High-dose antioxidants inhibit expression of c-myc, N-myc and H-ras [5–7] and the activity of protein kinase C [8,9]. These changes are considered growth inhibitory signals for cancer cells. In addition, high-dose antioxidants increase the expression of transforming growth factor-ß (TGF-ß) mRNA, TGF-ß protein and its secretion [10] and the expression of p21 and wild-type p53 [6,11], all of which are considered growth inhibitory signals for tumor cells. In addition, -TS induces Fas-mediated apoptosis in estrogen receptor-negative human breast cancer cells [12], and converts Fas-resistant human breast cancer cells to a Fas-sensitive phenotype [13]. FAS (also known as CD95 or APO-1) is a member of the TNF receptor and NGF receptor superfamily and regulates apoptosis. -TS also inhibits phosphorylation and transactivation of E2F, a transcriptional factor that is important in the regulation of cell proliferation [14]. Beta-carotene has been demonstrated to increase the expression of the connexin gene in cancer cells [15]. This finding indicates that ß-carotene treatment restores one of the features of normal cells, since the connexin gene codes for a gap junction protein that holds two normal cells together. The type and extent of the effects of high-dose antioxidants on tumor cells depend on the type and form of antioxidants, as well as the type of tumor cell.
At low-doses, certain individual antioxidants can stimulate the growth of some cancers [16–18]. For example, vitamin C at a dose of 50 µg/mL stimulates the growth of human parotid carcinoma cells (Fig. 2) and human leukemic cells in culture [17]. Such low doses have no significant effect on the growth of other cancer cells [16]. Low doses of synthetic ß-carotene increased the incidence of lung cancer among male heavy cigarette smokers [19]. The mechanisms of stimulation of cancer cell growth by low dose individual antioxidants are unknown. Because there is a distinct difference between low-dose and high-dose effects of certain antioxidants such as vitamin E, C and carotenoids [1,2], and because the individual antioxidants when oxidized can act as radicals, use of individual antioxidants alone for any health benefit on a long-term basis has no scientific rationale.
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Fig. 2. Effect of vitamin C on growth of human tumorigenic parotid acinar cells in culture (2HPG1). Cells (100,000/60 mm dish) were plated in tissue culture dishes, and freshly prepared sodium ascorbate solution at various concentrations was added 24 hours later. Freshly prepared sodium ascorbate solution and medium were changed after two days of treatment. Growth was determined after three days of treatment. Each value (mean ± SEM) represents an average of nine samples [16].
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Single vs. Multiple
We have demonstrated that a mixture of four antioxidants (13-cis-retinoic acid, sodium ascorbate, -TS and polar carotenoids without any ß-carotene activity) markedly inhibits the growth of human melanoma cells in culture [20]. These antioxidants individually had no effect on the growth of these tumor cells (Table 2). Doubling the dose of one of the antioxidants (vitamin C) further reduced the growth of tumor cells in vitro [20]. A mixture of four antioxidants was also more effective than the single antioxidant in reducing the growth of human parotid carcinoma cells in culture (Table 3) [16]. This observation is important because it experimentally indicates that a mixture of antioxidants could be more effective than a single antioxidant in reducing tumor growth. If one examines the fact that these antioxidants, in part, have different mechanisms of action and different efficacy depending upon the intra- and extracellular environment, the above results could have been predicted. This study also revealed that the use of multiple antioxidants might avoid the toxicity produced during treatment of certain human cancers with a single antioxidant at very high doses. A preliminary clinical trial in patients with non-small cell lung carcinoma demonstrated that the tumor response of patients receiving carboplatin and paclitaxel together with high doses of vitamin C, vitamin E and ß-carotene was much better than in patients receiving carboplatin and paclitaxel alone (Pathak et al., Table 4, unpublished data).
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Table 4. Effect of Multiple Antioxidants in Combination with Carboplatin and Paclitaxel on Tumor Response in Patients with Non-Small Lung Carcinoma
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Normal vs. Cancer cells
High-dose antioxidants individually have either no effect on normal cells or produce relatively less growth inhibition than on cancer cells in culture. However, high-dose antioxidants markedly inhibit the growth of different rodent and human cancer cells in vivo and in vitro. This issue has been recently reviewed [1–3,21] and recent studies have confirmed these observations. For example, -TS induces apoptosis in human prostate cancer cells, but not in normal prostate cells in vitro [22]. -TS decreases accumulation of mitotic cells in three human cancer cell lines, but not in normal human fibroblasts (Fig. 3) [23]. Furthermore, -TS induces chromosomal damage in human cervical cancer cells and in human ovarian cancer cells, but not in normal human fibroblasts (Fig. 4) [24]. High doses of individual antioxidants such as retinoids, vitamin C, ß-carotene and vitamin E have been used in rodents and humans without any effects on proliferating cell systems [6,11,20–21,25–31], while exhibiting varying levels of anti-tumor activity. Low-dose antioxidants also produce no significant effect on the growth of normal cells in vitro or in vivo. The reasons for these differential effects of antioxidants on normal and cancer cells are unknown. In the case of vitamin C, the higher sensitivity of tumor cells may be related to higher intracellular accumulation of this antioxidant. In the case of -TS, the higher sensitivity of tumor cells may due to acquired greater sensitivity, since both tumor and cancer cells accumulate similar intracellular levels of this antioxidant (Table 5).
One study demonstrated that tumor cells in vivo are more sensitive to antioxidant deficiency (vitamin A and E) than normal cells with respect to growth inhibition [32]. All normal and tumor cells require certain amounts of antioxidants for their growth and survival. Therefore, a deficiency of any one of them could retard the growth of both tumor cells and normal cells. It is possible that tumor cells exhibit greater sensitivity to a deficiency of antioxidant vitamins than do normal cells. In any case, such observations have no therapeutic relevance in human cancer because a deficiency of vitamin E or vitamin A will cause severe neurological damages, some of which can be irreversible. It should be pointed out that vitamin E deficiency is difficult to induce in humans.
Treatment Time
Antioxidant treatment for a short period of time (a few hours) may not inhibit the growth of cancer cells, whereas the treatment of cancer cells for a longer period of time (24 hours or more) with the same dose of antioxidants may cause growth inhibition. Because of the relative instability of antioxidants in a growth medium and because growth medium is depleted of certain essential nutrients, it is necessary to change the growth medium and antioxidants every two days after initial treatment. While investigating the effect of antioxidants in combination with standard cancer therapeutic agents, it is essential to consider not only total time of treatment, but also the time schedule of addition of antioxidants in relation to addition of therapeutic agents. Generally, cells are treated with antioxidants before, after, or before and after treatment with radiation or chemicals. Results obtained from each of the above treatment times may differ qualitatively and quantitatively from each other. For example, a treatment time of a few hours with an antioxidant before or after treatment with therapeutic agents may not increase the growth-inhibitory effects of these agents on tumor cells. However, a treatment of three days or more under the same experimental conditions may enhance the growth-inhibitory effects of therapeutic agents on cancer cells. Therefore, data on growth inhibition of normal and cancer cells obtained after treatment with multiple antioxidants before and after therapeutic agents for a longer period of time in vitro or in vivo may be more relevant to cancer treatment than use of multiple antioxidants after treatment for a shorter period of time.
Action of Antioxidants Other Than Free Radical Scavenging
Recent studies clearly indicate that some of the actions of antioxidants are not related to scavenging free radicals [33]. For example, ß-carotene increases the expression of the connexin gene in cancer cells, but other antioxidants do not produce this effect [15]. Vitamin E causes changes in the expression of certain genes, whereas agents with only antioxidant activity do not cause this effect [1].
All Antioxidants Do Not Produce Similar Biological Effects on Cancer Cells
The efficacy of antioxidants is dependent upon the cellular environment. For example, ß-carotene acts as a more efficient quencher of oxygen free radicals in comparison to other antioxidants [34]. ß-carotene acts as an effective scavenger of free radicals at reduced oxygen pressure, whereas -tocopherol is most effective at high oxygen pressure [35]. ß-carotene increases the expression of the connexin gene, whereas vitamin A does not [15]. ß-carotene and vitamin C prevent autooxidation of -tocopherol [36].
-TS acts as a more effective antioxidant than -tocopherol [37]. Vitamin C is an effective antioxidant in an aqueous environment, whereas vitamin A, ß-carotene and vitamin E are effective antioxidants in a lipid environment. Vitamin A induces cell differentiation in some tumor cells of epithelial origin [38,39], whereas ß-carotene and -TS do not. -TS and ß-carotene induce differentiation in murine melanoma cells [40,41], whereas vitamin C or vitamin A does not. Vitamin C inhibits the growth of tumor cells but does not cause differentiation [29,42]. These studies indicate that all antioxidants do not produce similar effects on cancer cells.
Effects of Individual Antioxidants in Combination with Standard Tumor Therapeutic Agents
The direct interaction between antioxidants and cancer therapeutic agents can initially best be tested on cancer cells in culture. Several cell culture studies reveal that vitamin C, -TS, -tocopheryl acetate, vitamin A (and its derivatives) and polar carotenoids enhance the growth inhibitory effect of most of the standard therapeutic agents (radiation and chemotherapy) on some cancer cells in culture [1]. The extent of this enhancement depends on the dose and form of the vitamin, the dose and type of chemotherapeutic agent and the type of tumor cells. Some examples of antioxidant-induced enhancement of the effect of irradiation and chemotherapeutic agents are described below.
-TS enhances the effect of irradiation on neuroblastoma cells in culture (Fig. 5). An aqueous form of vitamin E, -tocopheryl acetate, enhances the effect of vincristine on neuroblastoma cells in culture (Fig. 6). Vitamin C enhances the effect of 5-flurouracil (5-FU) on neuroblastoma cells in culture (Fig. 7). A few in vivo studies support the concept that antioxidants selectively enhance the effect of standard therapy on tumor cells by increasing tumor response. For example, vitamin A (retinyl palmitate) or synthetic ß-carotene at doses ten fold higher than the RDA for these nutrients, in combination with x-irradiation or cyclophosphamide, increased the cure rate from 0 to over 90% in mice with transplanted adenocarcinoma of the breast [25]. A recent study using a thiol-containing antioxidant, pyrrolidinedithiocarbamate (PDTC), and a water-soluble vitamin E analogue (6-hydroxy-2,5,7,8-tetrameythylchroman-2-carboxylic acid) demonstrated that antioxidant treatment enhanced the antitumor effects of 5-flurouracil (5-FU) and doxorubicin in vitro against several cancer cell lines, as well as the effect of 5-FU in vivo against two colorectal cancer cell lines [11]. The synthetic retinoid, fenretinide, is effective against a human ovarian carcinoma xenograft and potentiates cisplatin activity [43]. The combination of 13-cis retinoic acid and -2a interferon enhances the levels of radiation-induced growth inhibition in human head and neck squamous cell carcinoma in vitro [44].
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Fig. 5. Neuroblastoma cells (NBP2) were plated in tissue culture dishes (60 mm), and the cells were gamma-irradiated 24 hours after plating. Vitamin E succinate or the solvent (ethanol 0.25% and sodium succinate 5 µg/mL) wag added immediately before irradiation. The drugs and medium were changed after two days of treatment. The number of cells per dish was determined after three days of treatment. Each experiment was repeated at least twice involving three samples per treatment. The average value (172 ± 7 x 104) of untreated control NB cells was considered 100%, and the growth in treated cultures was expressed as a % of untreated controls. The bar at each point is standard error of the mean [1].
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Fig. 6. Neuroblastoma cells (NBP2) (50,000 per dish) were plated in tissue culture dishes (60 mm), and vincristine and aqueous preparation of vitamin E (dl--tocopheryl acetate) were added 24 hours later. Drugs and medium were changed two days after treatment. The cell number and the number of trypan blue-stained cells were determined three days after treatment. The number of stained cells was subtracted from the total number of cells to obtain viable cells per dish. The average of control cultures was considered 100%. Each value represents an average of at least six samples. The bar at each point is standard deviation. The bars not shown in figure were equal to sizes of symbol [1].
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Fig. 7. Neuroblastoma cells (50,000 per dish) were plated in tissue culture dishes (60 mm), and 5-fluorouracil (5-FU) (0.08 µg/mL) plus sodium ascorbate or sodium ascorbate alone was added 24 hours after plating. The drug and medium were changed every day, and the number of cells per dish was determined three days after treatment. Each value represents the mean of six to nine samples ± standard deviation [42].
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The effect of individual antioxidant vitamins in combination with x-irradiation or chemotherapeutic agents has not been tested in human tumors in vivo in a systematic manner. However, some studies reveal that certain antioxidants in combination with irradiation and chemotherapeutic agents may be beneficial in the management of human tumors. Eighteen non-randomized patients with small cell lung cancer received multiple antioxidant treatment with chemotherapy and/or radiation. The median survival time was markedly enhanced and patients tolerated chemotherapy and irradiation well [45]. Similar observations were made in several private practice settings [46]. A randomized trial with non-small cell lung carcinoma patients revealed that the tumor response in groups receiving chemotherapy plus multiple antioxidants was better than that observed in groups receiving chemotherapy alone (Table 4). ß-Carotene supplementation reduced radiation therapy and chemotherapy-induced oral mucositis without interfering with their efficacy on tumor cells [47]. Retinoic acid and interferon enhanced the effect of irradiation on locally advanced carcinoma of the cervix [48]. A mixture of antioxidants reduced radioimmunotherapy-induced myelosuppression in mice without interfering with the treatment efficacy in reducing tumor growth [49].
Many standard therapeutic agents mediate their effects, in part, by generating excessive amounts of free radicals that damage both normal and cancer cells. Therefore, some suggest that the use of high doses of antioxidant vitamins during standard cancer therapy might be harmful since they might protect both normal and cancer cells against the cell killing effects of tumor therapeutic agents [4]. Available experimental studies indicate that this concern has no scientific basis. For example, vitamin C, -TS and 13-cis-RA individually enhance the growth inhibitory effect of x-irradiation and certain chemotherapeutic agents on tumor cells in culture and in vivo [1,2]. This is a direct demonstration that antioxidants do not protect cancer cells against the growth-inhibitory effect of standard therapy. In fact, they enhance the growth inhibitory effects on tumor cells. The exact reasons for the differential effects of antioxidants in combination with tumor therapeutic agents are unknown. However, some of them are listed below. Cancer cells accumulate more vitamin C than normal cells [50,51] and this may account for the selective damage of cancer cells by vitamin C. Cancer cells and normal cells accumulate similar levels of -TS [24], but tumor cells are more sensitive to -TS than normal cells. This finding indicates that greater sensitivity of tumor cells to -TS is developed during transformation. Antioxidants such as retinoic acid reduce repair of potentially lethal damage in cancer cells more than in normal cells [52]. The greater sensitivity of cancer cells to antioxidants is responsible for initiating a series of genetic and epigenetic alterations that lead to differentiation, growth inhibition and apoptosis after treatment with antioxidants. The sensitivity of normal cells to antioxidants does not change. Therefore, no growth-inhibition is observed after treatment with antioxidants.
Effect of a Mixture of Antioxidant Vitamins in Combination with Certain Chemotherapeutic Agents
A mixture of antioxidants containing retinoic acid, vitamin C, -TS and polar carotenoids in combination with 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboximide (DTIC), tamoxifen, cis-platin or interferon--2a inhibited the growth of human melanoma cells in culture more than that produced by the individual agents (Table 6). This finding indicates that multiple antioxidants are also effective in enhancing the effect of certain chemotherapeutic agents on cancer cells. No such studies have been performed on normal cells.
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Table 6. Enhancement of the Effect of Certain Chemotherapeutic Agents by a Mixture of Four Antioxidants on Human Melanoma Cells in Culture
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Efficacy of Individual Antioxidants in Combination with Hyperthermia
Hyperthermia alone, or in combination with radiation, is primarily used in the management of local tumors in which all other standard modalities have failed. Variable improvements in transient tumor control have been observed. The temperatures used range from 43°C to 45°C. Hyperthermia, for the most part, has not proven to be of any significant value in improving the cure rate or survival time, but has proven to be of some value in improving the quality of life for a variable period of time. Therefore, the current treatment approaches must be altered from local hyperthermia at higher temperatures to whole-body hyperthermia at lower temperatures that can be tolerated without side effects. We have reported [53,54] that -TS markedly increased the effect of low temperature (41°C) and high temperature (43°C) hyperthermia on neuroblastoma cells in culture (Table 7). We propose that multiple antioxidants in combination with hyperthermia (local or whole-body) may further improve the efficacy of hyperthermia in the treatment of human cancer.
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Table 7. Effect of Alpha Tocopheryl Succinate (-TS) on Hyperthermia-Induced Growth Inhibition in Neuroblastoma Cells in Culture
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Effect of Individual Antioxidant Vitamins in Combination with Certain Biological Response Modifiers
We have reported [55] that -TS and polar carotenoids markedly enhance the levels of cAMP-induced terminal differentiation in neuroblastoma cells (Fig. 8) and melanoma cells (Fig. 9) in cultures [56]. In addition, -TS also enhances the growth-inhibitory effect of sodium butyrate (Fig. 10) [57] and interferon-2b [20] on neuroblastoma and human melanoma cells. Retinoic acid in combination with interferon-2a is highly active in the treatment of squamous cell carcinoma of the cervix in humans [48], suggesting that it can enhance the growth-inhibitory effect of some biological response modifiers.
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Fig. 8. Photomicrographs of neuroblastoma cells (NBP2) in culture after treatment with RO20-1724 and ß-carotene. Control cells (a) four days after plating (50,000 cells/60mm dish), showing mostly round cells; ß-carotene (20 µg/mL)-treated cells (b) four days after treatment showing no significant change in morphology; RO20-1724 (200 µg/mL)-treated cells (c) four days after treatment revealing increased number of cells with neurites; cells treated with RO20-1724 plus ß-carotene (d) for a period of four days showing more differentiated cells than those produced by RO20-1724 treatment alone; cells treated with RO20-1724 plus ß-carotene for a period of eight days (e) and (f) 11 days [55].
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Fig. 9. Photomicrographs of murine melanoma were taken four days after treatment. Control culture contained cells with varied morphology (a). The melanoma cells treated with vitamin E succinate (b) were elongated, had long cytoplasmic processes, and were arranged alongside each other. Melanoma cells treated with RO20-1724 (c) were large and elongated, had some long processes, and were arranged alongside each other. A combination of RO20-1724 and vitamin E succinate (d) increased the level of morphologic differentiation more than that produced by individual agents [56].
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Fig. 10. Effect of d--tocopheryl succinate (vitamin E succinate) in combination with sodium butyrate on the growth of neuroblastoma cells in culture. Cells (50,000 cells/60 mm dish) were plated in tissue culture dishes, and vitamin E succinate and sodium butyrate were added one after another 24 hours later. Fresh growth medium and agents were changed at two days after treatment and growth was determined at three days after treatment. Each value represents an average of six samples. The bar at each point is SEM [57].
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Reduction of Toxicity of Standard Tumor Therapeutic Agents by Individual and Multiple Antioxidants
Another part of our proposed hypothesis is that antioxidant vitamins in combination with standard therapeutic agents may reduce the toxicity of these agents on normal cells. Several studies using animal models (primarily rats and rabbits) also support this part of the hypothesis [1]. Vitamin E reduces bleomycin-induced lung fibrosis [58], adriamycin-induced cardiac toxicity [59–62] and adriamycin-induced skin necrosis [63]. Vitamin E also reduces adriamycin-induced toxicity in liver, kidney and intestinal mucosa [64]. Some studies have demonstrated that vitamin E protects normal tissue in vivo against radiation damage [65–67]. Another study has reported that ß-carotene and vitamin A (retinyl palmitate) reduce the adverse effects of x-irradiation and cyclophosphamide in rats. Vitamin C reduces the adverse effects of some chemotherapeutic agents on normal cells [25], such as those from adriamycin [68]. Vitamin C, -TS and RA reduce bleomycin-induced chromosomal breakage [69]. In addition, a combination of pentoxifylline and tocopherol reduced radiation-induced fibrosis in patients receiving radiation therapy [70]. Pretreatment with vitamin E, vitamin C and ß-carotene protected normal cells in mice against radiation damage [71]. However, vitamin C alone at very high doses could enhance the effect of irradiation on normal cells [71]. For this and other reasons, we do not recommend use of high-dose vitamin C alone in the treatment of cancer. Administering a mixture of antioxidants after irradiation also reduced radiation damage to normal cells. This finding indicates that these antioxidants enhance the repair of potentially lethal damage in normal cells. This is in contrast to cancer cells in which the repair of potential lethal damage is impaired by retinoic acid [52]. In another study [49], pretreatment of mice with vitamin E, C and ß-carotene reduced myelosuppression induced by radioimmunotherapy without adversely affecting the efficacy of this therapy on tumor cells. Vitamin E and vitamin C supplements reduced the tamoxifen-induced hyperlipidemia in patients with breast cancer [72].
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PROPOSED PROTOCOL FOR THE USE OF MICRONUTRIENTS, DIET AND LIFESTYLE MODIFICATIONS IN COMBINATION WITH STANDARD CANCER THERAPY
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The scientific rationale for the proposed protocols is discussed in detail in a recent publication [2]. The micronutrient supplement protocol is divided into two categories: active treatment phase and maintenance phase. During the active treatment phase, daily antioxidants are given orally before, during and for one month after treatment with standard therapeutic agents. During the maintenance phase (lifetime), antioxidants are taken daily at reduced doses. The micronutrient protocol contains supplements described below. Multiple antioxidant preparations include B-vitamins and appropriate minerals but not iron, copper and manganese, because these three minerals interact with vitamin C to produce free radicals. A brand name, Sevak (Scientific Nutrition, Inc., Oakland, California), which contains the above ingredients, is being sold commercially, and is in clinical trial. An additional 8 grams of vitamin C in the form of calcium ascorbate is recommended. Doses of vitamin C at 10 grams or more have been used in human cancer treatment without toxicity [29,73]. This form of vitamin C was selected because ascorbic acid at high doses can upset the stomach in some patients [73]. Calcium ascorbate rather than sodium ascorbate was selected because sodium ascorbate at high doses can increase the molarity of urine in the bladder and increase the risk of chemically induced bladder cancer in animals due to chronic irritation [74]. An additional 800 IU of natural vitamin E in the form of -TS is recommended. This form of vitamin E is the most potent form of vitamin E both in vitro and in vivo [1,2]. The natural form of vitamin E is used because animal studies demonstrate that various organs selectively pick up the natural form of vitamin E over the synthetic form [75]. An additional 60 mg/day of natural ß-carotene is recommended. The natural form of ß-carotene was selected because it is more active. For example, natural ß-carotene protects against radiation-induced transformation in vitro, whereas synthetic ß-carotene is ineffective [76].
All micronutrient supplements described above should be taken orally and in divided doses, one in the morning and one in the evening. The rationale for taking micronutrients twice a day is that the biological half-life of most antioxidants is about 6–12 hours. Micronutrient supplements can be started at least 48 hours prior to standard therapy and should be continued for one month after completion of standard therapy. Thereafter, the maintenance phase begins in which additional doses of vitamin C, vitamin E and ß-carotene can gradually (over a 4-week period) be reduced to half the levels of therapeutic doses. Such maintenance doses of micronutrients may reduce the risk of a second primary cancer among survivors. Dr. Jae Ho Kim of Henry Ford Hospital, Detroit has completed a preliminary clinical trial of the proposed micronutrient protocol and another is in progress at the Cancer Center of America under the direction of James Stark. The results of these studies have yet to be published.
Diet and Lifestyle Modifications
A low fat (10% of calories from fat), high fiber (25–30 grams from fruits, vegetables and cereals) diet should be continued during and after standard treatment, and continued throughout life. Lifestyle changes include cessation of tobacco smoking or consumption of tobacco products, reduced consumption of caffeine and alcoholic beverages, increased daily exercise, and reduced physical and mental stress.
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DO SOME ANTIOXIDANTS PROTECT CANCER CELLS AGAINST DAMAGE PRODUCED BY FREE RADICALS?
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Researchers have proposed that antioxidants may protect cancer cells against free radical damage, and therefore, should not be used during radiation or chemotherapy [4]. This proposal is based on the following assumptions: (a) tumor and normal cells respond to antioxidants at all doses in the same manner; (b) since most of the damage by radiation and most chemotherapeutic agents on normal and cancer cells are caused by free radicals; antioxidants must protect both normal and cancer cells in the same manner; (c) since certain antioxidants such as SH-compounds (cysteamine, glutathione and N-acetylcysteine) protect normal and cancer cells against free radical damage [77,78], other antioxidants such as retinoic acid, vitamin E, vitamin C and carotenoids must do the same; (d) since vitamin C accumulates more in cancer cells than in normal cells [50,51], it may protect cancer cells against free radical damage; and (e) since tumor cells are more sensitive to vitamin A and E deficiency than normal cells (with respect to growth inhibition) [32], supplementation with antioxidants may protect cancer cells against free radical damage. However, experimental data described in the previous sections indicate that none of these assumptions are supported by in vivo or in vitro studies. It is possible that individual antioxidants alone at low doses when given before treatment may protect both normal and cancer cells against free radical damage. However, because no such data are available at the present time, we do not recommend low doses of individual or multiple antioxidants (vitamins A, C, E, and carotenoids) as an adjunct to standard therapy. We also do not recommend SH-compounds at any doses during standard cancer therapy because they may protect both normal and cancer cells against free radical damage. Thus, substantial data, such as those discussed in this review, support our hypothesis that high-dose antioxidants may enhance the effect of radiation and chemotherapeutic agents selectively on tumor cells, and that they may or may not protect normal cells against such damage.
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CONCLUSION
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Substantial laboratory data and limited human studies indicate that supplementation with high-dose multiple micronutrients, including appropriate antioxidants (vitamin C, -tocopheryl succinate, and natural ß-carotene), as an adjunct to standard or experimental therapy (hyperthermia and biological response modifiers), may improve their efficacy by increasing tumor response and decreasing toxicity. Clinical trials on this issue are in progress. The responses of tumor cells to antioxidants differ from those of normal cells. Antioxidants, in part, have different mechanisms of action on tumor cells. In addition, some antioxidants, depending upon doses, can produce a bi-phasic effect on certain tumor cells. Additional mechanistic studies on antioxidants alone and in combination with standard tumor therapeutic agents are needed.
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ACKNOWLEDGMENTS
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This work was supported by the Shafroth Memorial Fund.
Received April 26, 2001.
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REFERENCES
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ABSTRACT
INTRODUCTION
