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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

| ABSTRACT

TOP ABSTRACT INTRODUCTION EFFICACY OF CANCER THERAPY EFFECT OF ANTIOXIDANTS ON... PROPOSED PROTOCOL FOR THE... DO SOME ANTIOXIDANTS PROTECT... CONCLUSION REFERENCES

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.

| INTRODUCTION

TOP ABSTRACT INTRODUCTION EFFICACY OF CANCER THERAPY EFFECT OF ANTIOXIDANTS ON... PROPOSED PROTOCOL FOR THE... DO SOME ANTIOXIDANTS PROTECT... CONCLUSION REFERENCES

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.

| EFFICACY OF CANCER THERAPY

TOP ABSTRACT INTRODUCTION EFFICACY OF CANCER THERAPY EFFECT OF ANTIOXIDANTS ON... PROPOSED PROTOCOL FOR THE... DO SOME ANTIOXIDANTS PROTECT... CONCLUSION REFERENCES

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.

| EFFECT OF ANTIOXIDANTS ON CANCER CELLS

TOP ABSTRACT INTRODUCTION EFFICACY OF CANCER THERAPY EFFECT OF ANTIOXIDANTS ON... PROPOSED PROTOCOL FOR THE... DO SOME ANTIOXIDANTS PROTECT... CONCLUSION REFERENCES

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.

View larger version (164K): [in this window] [in a new window] | Fig. 1. Melanoma cells (105) were plated in tissue culture dishes (60 mm), and d--tocopheryl succinate (-TS) and sodium succinate plus ethanol were added to separate cultures 24 hours after plating. Drugs and medium were changed at two and three days after treatment. Photomicrographs were taken four days after treatment. Control cultures showed fibroblastic cells as well as round cells in clumps (a); cultures treated with ethanol (1%) and sodium succinate (5–6 µg/mL) also exhibited fibroblastic morphology with fewer round cells (b); -TS-treated cultures 5 µg/mL (c), and 6 µg/mL (d) showed a dramatic change in morphology [41].

View this table: [in this window] [in a new window] | Table 1. Efficacy of Retinoids in the Treatment of Human Tumors

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.

View larger version (11K): [in this window] [in a new window] | 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].

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).

View this table: [in this window] [in a new window] | Table 2. Effect of a Mixture of Four Antioxidants on Growth of Human Melanoma Cells in Culture

View this table: [in this window] [in a new window] | Table 3. Effect of a Mixture of Four Antioxidants on Growth of Human Tumorigenic Parotid Acinar Cells in Culture

View this table: [in this window] [in a new window] | Table 4. Effect of Multiple Antioxidants in Combination with Carboplatin and Paclitaxel on Tumor Response in Patients with Non-Small Lung Carcinoma

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).

View larger version (35K): [in this window] [in a new window] | Fig. 3. Effects of -TS on mitotic accumulation in three human cancer cell lines and three normal human fibroblasts. Decreased mitotic accumulation is seen in cancer cells (A–C), but not in normal fibroblasts (D–F). Each point represents an average of six samples. Significant difference at p = 0.05 was observed in all tumor cell lines (A–C) at 20 µg/mL of -TS at all points in comparison to controls [23].

View larger version (28K): [in this window] [in a new window] | Fig. 4. Effect of d--tocopheryl succinate (-TS) on the level of radiation-induced chromosomal damage in human cervical cancer (HeLa cells), ovarian carcinoma cell lines (OVG1 and SKOV3) and in human normal skin fibroblasts (GM2149, HF19 and AG1522). -TS treatment alone increased chromosomal damage in all three cancer cell lines, but not in any normal cell lines. -TS treatment also enhanced the levels of radiation-induced chromosomal damage in cancer cells but it protected normal cells against such damage. The bar is standard error of the mean; and the difference between control and experimental groups in cancer cells, and between control (irradiation alone) and experimental groups (irradiation plus -TS) is significant at p = 0.05 [24].

View this table: [in this window] [in a new window] | Table 5. Accumulation of d--Tocopheryl Succinate (-TS) in Human Cervical Cancer (HeLa cells) and Normal Human Fibroblasts after 24 hours of Treatment with -TS

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].

View larger version (31K): [in this window] [in a new window] | 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].

View larger version (21K): [in this window] [in a new window] | 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].

View larger version (21K): [in this window] [in a new window] | 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].

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.

View this table: [in this window] [in a new window] | Table 6. Enhancement of the Effect of Certain Chemotherapeutic Agents by a Mixture of Four Antioxidants on Human Melanoma Cells in Culture

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.

View this table: [in this window] [in a new window] | Table 7. Effect of Alpha Tocopheryl Succinate (-TS) on Hyperthermia-Induced Growth Inhibition in Neuroblastoma Cells in Culture

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.

View larger version (123K): [in this window] [in a new window] | 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].

View larger version (113K): [in this window] [in a new window] | 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].

View larger version (25K): [in this window] [in a new window] | 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].

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].

| PROPOSED PROTOCOL FOR THE USE OF MICRONUTRIENTS, DIET AND LIFESTYLE MODIFICATIONS IN COMBINATION WITH STANDARD CANCER THERAPY

TOP ABSTRACT INTRODUCTION EFFICACY OF CANCER THERAPY EFFECT OF ANTIOXIDANTS ON... PROPOSED PROTOCOL FOR THE... DO SOME ANTIOXIDANTS PROTECT... CONCLUSION REFERENCES

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.

| DO SOME ANTIOXIDANTS PROTECT CANCER CELLS AGAINST DAMAGE PRODUCED BY FREE RADICALS?

TOP ABSTRACT INTRODUCTION EFFICACY OF CANCER THERAPY EFFECT OF ANTIOXIDANTS ON... PROPOSED PROTOCOL FOR THE... DO SOME ANTIOXIDANTS PROTECT... CONCLUSION REFERENCES

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.

| CONCLUSION

TOP ABSTRACT INTRODUCTION EFFICACY OF CANCER THERAPY EFFECT OF ANTIOXIDANTS ON... PROPOSED PROTOCOL FOR THE... DO SOME ANTIOXIDANTS PROTECT... CONCLUSION REFERENCES

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.

| ACKNOWLEDGMENTS

This work was supported by the Shafroth Memorial Fund.

Received April 26, 2001.

| REFERENCES

TOP ABSTRACT INTRODUCTION EFFICACY OF CANCER THERAPY EFFECT OF ANTIOXIDANTS ON... PROPOSED PROTOCOL FOR THE... DO SOME ANTIOXIDANTS PROTECT... CONCLUSION REFERENCES

1. Prasad KN, Kumar A, Kochupillai MD, Cole WC: High doses of multiple antioxidant vitamins: Essential ingredients in improving the efficacy of standard cancer therapy. J Am Coll Nutr 18: 13–25, 1999.[Abstract/Free Full Text]
2. Prasad KN, Cole WC, Hovland P: Cancer prevention studies: Past, present and future. Nutrition 14: 197–210, 1998.[Medline]
3. Cole WC, Prasad KN: Contrasting effects of vitamins as modulators of apoptosis in cancer cells and normal cells: A review. Nutr Cancer 29: 97–103, 1997.[Medline]
4. Labriola D, Livingston R: Possible interactions between dietary antioxidants and chemotherapy. Oncology 13: 1003–1008, 1999.[Medline]
5. Prasad KN, Edwards-Prasad J: Expressions of some molecular cancer risk factors and their modification by vitamins. J Am Coll Nutr 9: 28–34, 1990.[Medline]
6. Schwartz JL: Molecular and biochemical control of tumor growth following treatment with carotenoids or tocopherols. In Prasad KN, Santamaria L, Williams RM (eds): "Nutrients in Cancer Prevention and Treatment." New Jersey: Humana Press, 287–316, 1995.
7. Amatruda TTD, Sidell N, Ranyard J, Koeffler HP: Retinoic acid treatment of human neuroblastoma cells is associated with decreased N-myc expression. Biochem Biophys Res Commun 126: 1189–95, 1985.[Medline]
8. Gopalakrishna R, Gundimeda U, Chen Z: Vitamin E succinate inhibits protein kinase C: Correlation with its unique inhibitory effects on cell growth and transformation. In Prasad K, Santamaria L, Williams R (eds): "Nutrients in Cancer Prevention and Treatment." Totowa, New Jersey: Human Press, 21–37, 1995.
9. Mahoney C, Azzi A: Vitamin E inhibits protein kinase C activity. Biochem Biophys Res Commun 154: 694–697, 1988.[Medline]
10. Kline K, Yu W, Zhao B: Vitamin E succinate: Mechanisms of action as tumor cell growth inhibitor. In Prasad K, Santamaria L, Williams R (eds): "Nutrients in Cancer Prevention and Treatment." New Jersey: Humana Press, 39–55, 1995.
11. Chinery R, Brockman JA, Peeler MO, Shyr Y, Beauchamp D, Coffey RJ: Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: A p53-independent induction of p21WAFI/CIPI via C/EBPb. Nature Med 3: 1233–1241, 1997.[Medline]
12. Turley JM, Fu T, Ruscetti FW, Mikovits JA, Bertolette DC, III, Birchenall-Roberts MC: Vitamin E succinate induces Fas-mediated apoptosis in estrogen receptor-negative human breast cancer cells. Cancer Res 57: 881–90, 1997.[Abstract/Free Full Text]
13. Yu W, Israel K, Liao QY, Aldaz CM, Sanders BG, Kline K: Vitamin E succinate (VES) induces Fas sensitivity in human breast cancer cells: role for Mr 43,000 Fas in VES-triggered apoptosis. Cancer Res 59: 953–61, 1999.[Abstract/Free Full Text]
14. Turley J, Ruscetti F, Kim S-J, Fu T: Vitamin E succinate inhibits proliferation of BT-20 human breast cancer cells: Increased binding of cyclic AMP negatively regulates E2F transactivation activity. Cancer Res 57: 2668–2675, 1997.[Abstract/Free Full Text]
15. Zhang LX, Cooney RV, Bertram JS: Carotenoids up-regulate connexin-43 gene expression independent of their provitamin A or antioxidant properties. Cancer Res 52: 5707–5712, 1992.[Abstract/Free Full Text]
16. Prasad KN, Kumar R: Effect of individual antioxidant vitamins alone and in combination on growth and differentiation of human non-tumorigenic and tumorigenic parotid acinar cells in culture. Nutr Cancer 26: 11–19, 1996.[Medline]
17. Park CH: Vitamin C in leukemia and preleukemia cell growth. Prog Clin Biol Res 259: 321–330, 1988.[Medline]
18. Cohen M, Bhagavan HN: Ascorbic Acid and Gastrointestinal Cancer. J Am Coll Nutr 14: 565–578, 1995.[Abstract]
19. Anonymous: The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group [see comments]. N Engl J Med 330: 1029–35, 1994.[Abstract/Free Full Text]
20. Prasad KN, Hernandez C, Edwards-Prasad J, Nelson J, Borus T, Robinson WA: Modification of the effect of tamoxifen, cis-platin, DTIC and interferon-a2b on human melanoma cells in culture by a mixture of vitamins. Nutr Cancer 22: 233–245, 1994.[Medline]
21. Prasad KN, Cole W, Prasad JE: Multiple antioxidant vitamins as an adjunct to standard and experimental therapies. Z Onkol/J Oncol 31: 4–11, 1999.
22. Israel K, Yu W, Sanders BG, Kline K: Vitamin E succinate induces apoptosis in human prostate cancer cells: role for Fas in vitamin E succinate-triggered apoptosis. Nutr Cancer 36: 90–100, 2000.[Medline]
23. Jha MN, Bedford JS, Cole WC, Edwards-Prasad J, Prasad KN: Vitamin E (d-a tocopheryl succinate) decreases mitotic accumulation in -irradiated human tumor, but not in normal cells. Nutr Cancer 35: 189–194, 1999.[Medline]
24. Kumar B, Jha MN, Cole WC, Bedford JS, Prasad KN: d-Alpha tocopheryl succinate (vitamin E) enhances radiation-induced chromosomal damage levels in human cancer cells, but reduces it in normal cells. J Am Coll Nutr, submitted, 2001.
25. Seifter E, Rettura A, Padawar J, Levenson SM: Vitamin A and ß-carotene as adjunctive therapy to tumor excision, radiation therapy and chemotherapy. In Prasad KN (ed): "Vitamins, Nutrition and Cancer." Basel: Karger, 1–19, 1984.
26. Garewal H: Beta-carotene and antioxidant nutrients in oral cancer prevention. In Prasad KN, Santamaria L, Williams RM (eds): "Nutrients in Cancer Prevention and Treatment." New Jersey: Human Press, 235–247, 1995.
27. Malafa MP, Neitzel LT: Vitamin E succinate promotes breast cancer dormancy and inhibits VEGF gene expression. Frontiers of Pharmacology and Therapeutics in 21st Century. New Delhi, India, pp 15–19, 1999.
28. Meyskens Jr FL: Role of vitamin A and its derivatives in the treatment of human cancer. In Prasad KN, Santamaria L, Williams RM (eds): "Nutrients in Cancer Prevention and Treatment." Totowa, New Jersey: Humana Press, 349–362, 1995.
29. Cameron E, Pauling L, Leibowitz B: Ascorbic acid and cancer. A review. Cancer Res 39: 663–681, 1979.[Abstract/Free Full Text]
30. Dreno B: Roferon-A (interferon alpha 2a) combined with Tigason (etretinate) for treatment of cutaneous T cell lymphomas. Stem Cells 11: 269–275, 1993.[Abstract]
31. Lippman SM, Parkinson DR, Itri LM, et al: 13-cis retinoic acid plus interferon -2a: Highly active systemic therapy for squamous cell carcinoma of the cervix. J Natl Cancer Inst 84: 241–245, 1995.[Abstract/Free Full Text]
32. Salganik R, Albright C, Rodgers J, et al: Enhancement of apoptosis and inhibbrain tumor growth in transgenic mice by depletion of antioxidants (abstract). American Society for Cell Biology, Annual Meeting, 1999. Wahington, D.C.: Am Soc Cell Biol, 444a, 1999.
33. Traber MG, Packer L: Vitamin E: beyond antioxidant function. American Journal of Clinical Nutrition 62: 1501S–1509S, 1995.[Abstract/Free Full Text]
34. Krinsky N: Antioxidant Functions of Carotenoids. Free Radical Biol & Med 7: 617–635, 1989.[Medline]
35. Vile GF, Winterbourn CC: Inhibition of Adriamycin Promoted Microsomal Lipid Peroxidation By ß-Carotene, -Tocopherol and Retinal At High and Low Oxygen Partial Pressure. FEBS Lett 238: 353–356, 1988.[Medline]
36. McCay PB: Vitamin E: Interactions With Free Radicals and Ascorbate. Ann Rev Nutr 5: 323–340, 1985.[Medline]
37. Carini R, Poli G, Dianzani MU, Maddix SP, Slater TF, Cheeseman KH: Comparative evaluation of the amount of the antioxidant activity of -tocopherol, -tocopherol polyethylene glycol 1000 succinate and -tocopherol succinate in isolated hepatocytes and liver microsomal suspensions. Biochem Pharmacol 39: 1597–1601, 1990.[Medline]
38. Sporn MB, Roberts AB: Role of retinoids in differentiation and carcinogenesis. Cancer Res 43: 3034–3040, 1983.[Free Full Text]
39. Carter CA, Pogribny M, Davidson A, Jackson CD, McGarrity LJ, Morris SM: Effects of retinoic acid on cell differentiation and reversion towards normal in human endometrial adenocarcinoma (RL95-2) cells. Anticancer Res 16: 17–24, 1996.[Medline]
40. Hazuka MB, Edwards-Prasad J, Newman F, Kinzie JJ, Prasad KN: Beta-carotene induces morphological differentiation and decreases adenylate cyclase activity in melanoma cells in culture. J Am Coll Nutr 9: 143–9, 1990.[Abstract]
41. Prasad KN, Edwards-Prasad J: Effect of tocopherol (vitamin E) acid succinate on morphological alterations and growth inhibition in melanoma cells in culture. Cancer Res 42: 550–555, 1982.[Abstract/Free Full Text]
42. Prasad KN, Sinha PK, Ramanujam M, Sakamoto A: Sodium ascorbate potentiates the growth inhibitory effect of certain agents on neuroblastoma cells in culture. Proc Natl Acad Sci USA 76: 829–832, 1979.[Abstract/Free Full Text]
43. Formelli F, Cleris L: Synthetic retinoid fenretinide is effective against a human ovarian carcinoma xenograft and potentiates cisplatin activity. Cancer Res 53: 5374–6, 1993.[Abstract/Free Full Text]
44. DeLaney TF, Afridi N, Taghian AG, et al.: 13-cis-retinoic acid with alpha-2a-interferon enhances radiation cytotoxicity in head and neck squamous cell carcinoma in vitro. Cancer Res 56: 2277–80, 1996.[Abstract/Free Full Text]
45. Jaakkola K, Lahteenmaki P, Laakso J, Harju E, Tykka H, Mahlberg K: Treatment with antioxidant and other nutrients in combination with chemotherapy and irradiation in patients with small-cell lung cancer. Anticancer Res 12: 599–606, 1992.[Medline]
46. Lamson DW, Brignall MS: Antioxidants in cancer therapy; Their actions and interactions with oncologic therapies. Alternative Med Rev 4: 304–329, 1999.
47. Mills EE: The modifying effect of beta-carotene on radiation and chemotherapy induced oral mucositis. Brit J Cancer 57: 416–417, 1988.[Medline]
48. Lippman SM, Kavanagh JJ, Parades M, Delgadillo F, Hong WK, Figuerda F, et al: 13-cis-retinoic acid (13-cRA), interferon 2a and radiotherapy for locally advanced cancer of cervix. Proc Am Soc Clin Oncol 12: 257, 1993.
49. Blumenthal RD, Lew W, Reising A, et al.: Anti-oxidant vitamins reduce normal tissue toxicity induced by radio-immunotherapy. Int J Cancer 86: 276–80, 2000.[Medline]
50. Hanck AB: Vitamin C and cancer. Prog Clin Biol Res 259: 307–20, 1988.[Medline]
51. Piyathilake CJ, Bell WC, Johanning GL, Cornwell PE, Heimburger DC, Grizzle WE: The accumulation of ascorbic acid by squamous cell carcinomas of the lung and larynx is associated with global methylation of DNA. Cancer 89: 171–6, 2000.[Medline]
52. Rutz H, Little J: Modification of radiosensitivity and recovery from x-ray damage in vitro, by retinoic acid. Int J Rad Oncol Biol Physics 16: 1285–1288, 1981.
53. Sahu SN, Prasad KN: Combined effect of adenosine 3',5'-cyclic monophosphate stimulating agents, vitamin E succinate, and heat on the survival of murine B-16 melanoma cells in culture. Cancer 62: 949–953, 1988.[Medline]
54. Rama BN, Prasad KN: Effect of hyperthermia in combination with vitamin E and cyclic AMP on neuroblastoma cells in culture. Life Sci 34: 2089–2097, 1984.[Medline]
55. Prasad KN, Kentroti S, Edwards-Prasad J, et al.: Modification of the expression of adenosine 3',5'-cyclic monophosphate-induced differentiated functions in neuroblastoma cells by beta-carotene and D-alpha-tocopheryl succinate. J Am Coll Nutr 13: 298–303, 1994.[Abstract]
56. Prasad KC: Induction of differentiated phenotypes in melanoma cells by a combination of an adenosine 3',5'-cyclic monophosphate stimulating agent and d--tocopheryl succinate. Cancer Lett 116: 17–22, 1989.
57. Rama BN, Prasad KN: Effect of dl-alpha-tocopheryl succinate in combination with sodium butyrate and cAMP-stimulating agents on neuroblastoma cells in culture. Int J Cancer 34: 863–867, 1984.[Medline]
58. Yamanaka N, Fukishima M, Koizumi K, Nishida K, Kato T, et al: Enhancement of DNA chain breakage by bleomycin and biological free radical producing systems. In DeDuve C, Hayashi T (eds): "Tocopherol, Oxygen and Biomembranes." New York: North Holland, 59–69, 1978.
59. Myers CE, McGuire W, Young R: Adriamycin: Amelioration of toxicity by alpha-tocopherol. Cancer Treatment Reports 60: 961–962, 1976.[Medline]
60. Sonnevald P: Effect of alpha tocopherol on cardiotoxicity of adriamycin in the rat. Cancer Treat Rep 62: 1033–1036, 1978.[Medline]
61. Van Vleet JF, Greenwood L, Ferands VJ, Rebar AH: Effect of selenium-vitamin E on adriamycin-induced cardiomyopathy in rabbits. Am J Vitamin Res 39: 997–1010, 1978.
62. Wang YM, Madanat FF, Kimball JC, Gieser CA, Ali MK, et al: Effect of vitamin E against adriamycin-induced toxicity in rabbits. Cancer Res 40: 1022–1027, 1980.[Abstract/Free Full Text]
63. Svingen BA, Powis A, Abbel PL, Scott M: Protection against adriamycin-induced skin necrosis in the rat by dimethylsulfoxide and alpha-tocopherol. Cancer Res 41: 3395–3399, 1981.[Abstract/Free Full Text]
64. Geetha A, Sankar R, Marar T, Devi CSS: Alpha tocopherol reduces doxorubicin-induced toxicity in rats-histological and biochemical evidences. Indian Physiol Pharmacol 34: 94–98, 1990.
65. Srinavasan V, Jacobs AL, Simpson SA, Weiss JF: Radioprotection by vitamin E. Effect on hepatic enzymes, delayed type hypersensitivity and post-irradiation survival in mice. In Meyskens FLJ, Prasad KN (eds): "Modulation and Mediations of Cancer Cells by Vitamins." Basel: Karger, 119–131, 1983.
66. Malick MA, Roy RM, Sternberg J: Effect of vitamin E on post-irradiation death in mice. Experientia 34: 1216–1217, 1978.[Medline]
67. Londer HM, Myers CE: Radioprotective effects of vitamin E (abstract). Am J Clin Nutr 31: 705a, 1978.
68. Fujita K, Shinpo K, Sato T, Niime H, Shamoto M, et al: Reduction of adriamycin-toxicity by ascorbate in mice and guinea pigs. Cancer Res 42: 309–316, 1982.[Abstract/Free Full Text]
69. Trizna Z, Schantz SP, Lee JJ, Spitz MR, Goepfert H, et al: In vitro protective effect of chemopreventive agents against bleomycin-induced genotoxicity in lymphoblastoid cell lines and peripheral lymphocytes of head and neck cancer patients. Cancer Detect Prev 17: 575–583, 1993.[Medline]
70. Delanian S: Striking regression of radiation-induced fibrosis by a combination of pentoxifylline and tocopherol. Br J Rad 71: 892–894, 1998.
71. Konopacka M, Widel M, Rzeszowska-Wolny J: Modifying effect of vitamins C, E and beta-carotene against gamma-ray-induced DNA damage in mouse cells. Mut Res 417: 85–94, 1998.[Medline]
72. Babu JR, Sundravel S, Arumugam G, Renuka R, Deepa N, Sachdanandam P: Salubrious effects of vitamin C and vitamin E on tamoxifen-treated women in breast cancer with reference to plasma lipid and lipoprotein levels. Cancer Lett 151: 1–5, 2000.[Medline]
73. Creagan ET, Moertel CG, O’Fallon JR: Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. N Engl J Med 301: 687–690, 1979.[Abstract]
74. Fukushima S, Imaida K, Shibata M-K, Tamano S, Kurata Y, Shirai T: L-ascorbic acid amplification of second-stage bladder carcinogenesis promotion by NaHCO3. Cancer Res 48: 6317–6320, 1988.[Abstract/Free Full Text]
75. Ingold KU, Burton GW, Foster DO, Hughes L, Lindsay DA, Webb A: Biokinetics of and discrimination between dietary RRR- and SRR-alpha-tocopherols in the male rat. Lipids 22: 163–172, 1987.[Medline]
76. Kennedy AR, Krinsky NI: Effects of retinoids, ß-carotene and canthaxanthene on U.V. and x-ray-induced transformation of C3H10T 1/2 cells in vitro. Nutr Cancer 22: 219–232, 1994.[Medline]
77. Prasad KN: "Handbook of Radiobiology," 2nd ed. Boca Raton, Fl: CRC Press, 1995.
78. Sinclair WK: Cysteamine: differential x-ray protective effect on Chinese hamster cells during the cell cycle. Science 159: 442–4, 1968.[Abstract/Free Full Text]

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