| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Center for Vitamins and Cancer Research (K.N.P., A.K., W.C.C.), Department of Radiology, School of Medicine, University of Colorado Health Sciences Center, Denver, CO
All India Institutes of Medical Sciences (V.K.), New Delhi, INDIA
Address reprint requests to: Kedar N. Prasad, PhD, UCHSC, Dept. of Radiology, Box C278, 4200 E. 9th Avenue, Denver, CO 80262
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONEFFICACY OF STANDARD TUMOR...EFFICACY OF EXPERIMENTAL CANCER...ANTI-CANCER PROPERTIES OF...ANTI-CANCER PROPERTIES OF...EFFICACY OF ANTIOXIDANTS IN...EFFICACY OF ANTIOXIDANT VITAMINS...ANTIOXIDANT VITAMINS IN...REDUCTION OF TOXICITY OF...DIET AND LIFESTYLE MODIFICATIONSREFERENCES |
|---|
-tocopheryl succinate), vitamin C (primarily sodium ascorbate) and carotenoids (primarily polar carotenoids) induce cell differentiation and growth inhibition to various degrees in rodent and human cancer cells by complex mechanisms. The proposed mechanisms for these effects include inhibition of protein kinase C activity, prostaglandin E1-stimulated adenylate cyclase activity, expression of c-myc, H-ras, and a transcription factor (E2F), and induction of transforming growth factor-ß and p21 genes. Furthermore, antioxidant vitamins individually or in combination enhance the growth-inhibitory effects of x-irradiation, chemotherapeutic agents, hyperthermia, and biological response modifiers on tumor cells, primarily in vitro. These vitamins, individually, also reduce the toxicity of several standard tumor therapeutic agents on normal cells. Low fat and high fiber diets can further enhance the efficacy of standard cancer therapeutic agents; the proposed mechanisms for these effects include the production of increased levels of butyric acid and binding of potential mutagens in the gastrointestinal tract by high fiber and reduced levels of growth promoting agents such as prostaglandins, certain fatty acids and estrogen by low fat. We propose, therefore, a working hypothesis that multiple antioxidant vitamin supplements together with diet and lifestyle modifications may improve the efficacy of standard and experimental cancer therapies. KEY TEACHING POINTS: • Supplemental antioxidants poteniate the efficacy of chemotherapy
• Supplemental antioxidants potentiate the efficacy of x-irradiation and hyperthermia
• Supplemental antioxidants induce differentiation in cancer cells
• Supplemental antioxidants regulate gene expression in cancer cells
Key words: differentiation, growth-inhibition, gene regulation, vitamin supplements, diet, lifestyle
Abbreviations: RA=retinoic acid • -TS=-tocopheryl succinate • -TA=-tocopheryl acetate • T=-tocopherol
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONEFFICACY OF STANDARD TUMOR...EFFICACY OF EXPERIMENTAL CANCER...ANTI-CANCER PROPERTIES OF...ANTI-CANCER PROPERTIES OF...EFFICACY OF ANTIOXIDANTS IN...EFFICACY OF ANTIOXIDANT VITAMINS...ANTIOXIDANT VITAMINS IN...REDUCTION OF TOXICITY OF...DIET AND LIFESTYLE MODIFICATIONSREFERENCES |
|---|
|
EFFICACY OF STANDARD TUMOR THERAPY PROTOCOLS |
|---|
|
TOPABSTRACTINTRODUCTIONEFFICACY OF STANDARD TUMOR...EFFICACY OF EXPERIMENTAL CANCER...ANTI-CANCER PROPERTIES OF...ANTI-CANCER PROPERTIES OF...EFFICACY OF ANTIOXIDANTS IN...EFFICACY OF ANTIOXIDANT VITAMINS...ANTIOXIDANT VITAMINS IN...REDUCTION OF TOXICITY OF...DIET AND LIFESTYLE MODIFICATIONSREFERENCES |
|---|
|
EFFICACY OF EXPERIMENTAL CANCER THERAPY PROTOCOLS |
|---|
|
TOPABSTRACTINTRODUCTIONEFFICACY OF STANDARD TUMOR...EFFICACY OF EXPERIMENTAL CANCER...ANTI-CANCER PROPERTIES OF...ANTI-CANCER PROPERTIES OF...EFFICACY OF ANTIOXIDANTS IN...EFFICACY OF ANTIOXIDANT VITAMINS...ANTIOXIDANT VITAMINS IN...REDUCTION OF TOXICITY OF...DIET AND LIFESTYLE MODIFICATIONSREFERENCES |
|---|
Before discussing the rationale for using multiple antioxidants vitamins together with modifications in diet and lifestyle in combination with standard therapy or experimental therapy in cancer treatment, it is essential to briefly describe the anticancer properties of individual antioxidant vitamins.
|
ANTI-CANCER PROPERTIES OF INDIVIDUAL ANTIOXIDANT VITAMINS |
|---|
|
TOPABSTRACTINTRODUCTIONEFFICACY OF STANDARD TUMOR...EFFICACY OF EXPERIMENTAL CANCER...ANTI-CANCER PROPERTIES OF...ANTI-CANCER PROPERTIES OF...EFFICACY OF ANTIOXIDANTS IN...EFFICACY OF ANTIOXIDANT VITAMINS...ANTIOXIDANT VITAMINS IN...REDUCTION OF TOXICITY OF...DIET AND LIFESTYLE MODIFICATIONSREFERENCES |
|---|
|
ANTI-CANCER PROPERTIES OF VITAMIN A AND ITS ANALOGS |
|---|
|
TOPABSTRACTINTRODUCTIONEFFICACY OF STANDARD TUMOR...EFFICACY OF EXPERIMENTAL CANCER...ANTI-CANCER PROPERTIES OF...ANTI-CANCER PROPERTIES OF...EFFICACY OF ANTIOXIDANTS IN...EFFICACY OF ANTIOXIDANT VITAMINS...ANTIOXIDANT VITAMINS IN...REDUCTION OF TOXICITY OF...DIET AND LIFESTYLE MODIFICATIONSREFERENCES |
|---|
|
Anti-Cancer Properties of Vitamin E (-Tocopherol)
Commercially, the forms of vitamin E available include d--tocopherol (-T) (natural) or dl--tocopherol (synthetic), mixed tocopherols, -tocopheryl acetate (-TA), -tocopheryl succinate (-TS) and -tocopheryl nicotinate (-TN). A water-soluble vitamin E analog (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, vitamin E) has become available for investigational use [18]. In addition, a synthetic preparation of -tocopheryl hemisuccinate [19], which is not hydrolyzed, has also become available for experimental use.
Before 1980, all animal and human studies utilized -T or -TA to investigate the effects of vitamin E on a given biological or physiological function primarily in vivo. Because of its relative lack of aqueous solubility, the mechanistic effect of this vitamin could not be investigated in cell culture systems. In 1982, we demonstrated, for the first time, that -TS is the most active form of vitamin E for inducing cell differentiation (Fig. 1), growth inhibition and cell death in murine melanoma cells in culture [20]. The potency of -TS was further confirmed on several human and rodent tumor cells in culture which include human promyoletic leukemia [21], murine and human neuroblastoma [22,23], rat glioma [22], murine and human melanoma [4,20], human parotid carcinoma [5], and human breast carcinoma [21,24]. This observation was also confirmed in animal cancer in vivo [25,26]. Even as an antioxidant, -TS was more potent than -tocopherol [27]. Water soluble preparations of vitamin E also reduce the growth of human colorectal cancer cells in vitro and in vivo [18] and in murine neuroblastoma and rat glioma cells in culture [28]. The exact reasons for the effectiveness of -TS or water soluble preparations of vitamin E on tumor cells in vitro are unknown. It may be due to increased intracellular accumulation of these forms of vitamin E in cancer cells. Indeed, when tumor cells were incubated in the presence of -TS, -TA, or -T for a period of 1 or 24 hours, only -TS was observed in an extraction for vitamin E by high performance liquid chromatography [22]. This suggested that -TS crossed cell membranes more readily than -TA or -T. For most tumors, natural and synthetic forms of -TS were equally effective, but for rat glioma (C-6) cells, the natural form of -TS was more effective than the synthetic form [22]. The higher biological efficacy of the natural form of vitamin E was further documented by the observation that various organs in the rat selectively accumulate the natural form of vitamin E more than the synthetic form when administered simultaneously [29].
|
-TS in cancer therapy was criticized on the grounds that all -TS will be hydrolyzed in the gut before absorption, and will therefore have the same biological effectiveness as -T. This conventional thinking was found to be incorrect by experiments with humans. Human melanoma patients who were consuming 800 I.U. of d--TS daily showed increased levels of -T (60 µg/ml) and significant amounts of -TS (6 µg/ml) in plasma (Prasad and Robinson, unpublished observation). The basal level of -T in human blood is about 6 to 10 µg/ml. This suggested that a portion of -TS is absorbed without hydrolysis and can become available to tumor cells for increased accumulation. A direct administration of -TS near the site of buccal carcinoma caused regression of the tumor, whereas -TA was ineffective [25,26]. -TS also inhibited the growth of human neuroblastoma tumor transplanted into athymic mice [23]. There was no evidence of damage to normal tissue in any of the in vivo studies with -TS. Thus, a few in vivo studies suggest that -TS selectively inhibits the growth of tumor cells. The exact mechanisms of action of -TS on cancer cells are unknown. However, increased accumulation of -TS intracellularly can increase the level of growth inhibitory signals. Indeed, -TS [30] and -T [31] inhibit protein kinase C activity and expression of c-myc and H-ras oncogenes [32], both of which are considered one of the growth regulatory signals. Alpha TS also increases the synthesis and release of transforming growth factor-ß which is considered one of the growth inhibitory signals [21] and inhibits the phophorylation and transactivation of E2F, which is considered one of the important components in the regulation of cell proliferation [24]. There is no evidence that -TS inhibits the growth of any normal dividing cells in vivo. This may be due to the fact that normal cells are considered to have strict homeostatic control for the uptake of antioxidant vitamins; and therefore, -TS does not accumulate in amounts which can inhibit the growth of these cells. The differential uptake of -TS between normal cells and cancer cells must be confirmed by additional experiments in vivo. Based on these results, we favor the use of d--TS for any clinical studies with vitamin E.
Anti-Cancer Properties of Carotenoids
There are over 1000 carotenoids found, so far, in nature; however, only a few of them occur in abundance in fruit and vegetables. These include ß-carotene (carrots), lycopene (tomatoes) and lutein (spinach). Among these, the most widely studied carotenoid is ß-carotene. Beta-carotene is available in synthetic and natural forms. Most of the clinical and experimental studies have been conducted with the synthetic form because it is cheaper and thought to be a more purified form of ß-carotene, exhibiting a single peak on HPLC analysis. On the other hand, natural ß-carotene might contain other carotenoids which would make the interpretation of any ß-carotene effect difficult. Recently, we observed that commercial preparations of synthetic ß-carotene may contain contaminants of relatively polar substances which absorb at 450 nm, and therefore are considered putative polar carotenoids [33]. In some preparations of synthetic ß-carotene, no peak corresponding to ß-carotene could be observed, but instead there was a multiplicity of peaks corresponding to putative polar carotenoids. Such polar carotenoid peaks were also present in preparations of natural ß-carotene. Our earlier studies [1,4,33] with synthetic ß-carotene preparations showed that ß-carotene can induce differentiation in murine melanoma cells, but can inhibit or stimulate the growth of human melanoma cells. It can also inhibit the growth of several other tumor cells in culture, and can stimulate the level of cAMP-induced differentiation of murine neuroblastoma cells in culture. However, HPLC analysis of the synthetic ß-carotene preparation which was used for these studies showed only the aforementioned polar carotenoids with the total absence of ß-carotene. Freshly dissolved and a 6-month-old sample of the preparation gave similar HPLC profiles and similar biological activity [33], suggesting that these polar carotenoids are very stable in ethanol solution. Synthetic forms of ß-carotene have been used by other investigators and they have shown to increase the expression of connexin gene, a gene which codes for the gap junction protein [34]. Several animal studies have utilized synthetic ß-carotene in cancer treatment experiments. For example, supplementation with high doses of ß-carotene caused slight regression of transplanted adenocarcinoma of breast in rat [8]. Administration of ß-carotene directly adjacent to the tumor site markedly inhibited the growth of oral carcinoma in hamsters [25,26]. Synthetic ß-carotene has been used in the treatment of oral leukoplakia in humans, and a marked regression was reported [35]. None of these studies measured their synthetic ß-carotene preparation by analytical HPLC for purity. Therefore, whether or not the above effects were due to ß-carotene and/or contaminants present in the preparation cannot be ascertained. On the contrary, they suggest that the role of polar carotenoids as contaminants in ß-carotene preparations in inducing growth inhibition or growth stimulation must be considered. Homogeneous preparations of synthetic ß-carotene dissolved in tetrahydrofuran has shown no effect on the growth of murine neuroblastoma cells in culture [33]. Preparations of natural ß-carotene reduced the radiation-induced transformation of mammalian cells in vitro, whereas a synthetic one did not [36]. This study also provided no evidence of the purity of the ß-carotene preparations. In our experience, natural ß-carotene preparations exhibited several peaks in addition to the ß-carotene as analyzed by HPLC [33]. Thus all experimental and clinical studies published on synthetic or natural ß-carotene in which the purity of the preparation before use was not reported must be considered invalid with respect to the role ß-carotene in modulating published biological functions. Nevertheless, ß-carotene, being an important antioxidant, should be used in the treatment of cancer and we favor the use of natural ß-carotene for this purpose.
Anti-Cancer Properties of B Vitamins
Most of the B vitamins have shown no direct anti-cancer activity. Supplementation with high doses of B6 can stimulate the growth of transplanted human lung cancer cells in nude mice [37]. Others have reported that B6 inhibits the growth of some tumor cells in vitro [38]. Nicotinamide (vitamin B3) increases radiation response of tumors in an animal model by increasing blood flow to tumor tissue [39,40R]. These studies further suggest that the use of single vitamins in cancer treatment could be counter productive. High doses of B6 (50 mg or more) could cause peripheral neuropathy. Nevertheless, supplementation with moderate doses of B vitamins is essential for maintaining optimal health.
Efficacy of a Mixture of Antioxidant Vitamins
Individual antioxidant vitamins produce varying degrees of tumor regression in vivo only at very high doses which frequently cause toxicity, especially with retinoid derivatives. At lower doses, they may be ineffective or stimulate the growth of cancer cells. Therefore, the use of single vitamins in cancer treatment has no biological or clinical merit. This led to the investigation of the effects of multiple antioxidants on the growth of cancer cells in vitro in order to demonstrate whether the individual vitamins can interact with each other to produce a higher degree of growth inhibition selectively on cancer cells than can be achieved by single vitamins at the same doses. We have reported (Table 2) that a mixture of four antioxidants (13-cis-retinoic acid, sodium ascorbate, d--tocopheryl succinate and polar carotenoids without any ß-carotene) markedly inhibited the growth of human melanoma cells in culture at doses where each component individually had no effect on growth [4]. This observation was considered important because it suggested, for the first time, that a mixture of vitamins could be more effective than single vitamins in reducing tumor growth. This study also revealed the possibility that lower doses of individual vitamins as part of a mixture can be used in cancer treatment and thereby avoid the possibility of the toxicity seen with the single vitamins at higher doses, or growth stimulation at lower doses. The mixture of four antioxidants produced similar results on human parotid carcinoma cells in reducing their growth [5] (Table 3). Vitamin C (100 µg), -TS (10 µg/ml), and RA (7.5 µg/ml) individually have no significant effect on the growth of tumor cells; however, polar carotenoids (10 µg/ml) reduced the growth to 60% of control. Doubling of the doses of one of the four vitamins in a vitamin mixture further reduced the growth of tumor cells in vitro. No well controlled studies on the effect of a mixture of four vitamins on the growth of animal tumors or human tumors have been performed. Therefore, preclinical and clinical studies using multiple vitamins at appropriate doses must be initiated.
|
|
|
EFFICACY OF ANTIOXIDANTS IN COMBINATION WITH STANDARD TUMOR THERAPEUTIC AGENTS |
|---|
|
TOPABSTRACTINTRODUCTIONEFFICACY OF STANDARD TUMOR...EFFICACY OF EXPERIMENTAL CANCER...ANTI-CANCER PROPERTIES OF...ANTI-CANCER PROPERTIES OF...EFFICACY OF ANTIOXIDANTS IN...EFFICACY OF ANTIOXIDANT VITAMINS...ANTIOXIDANT VITAMINS IN...REDUCTION OF TOXICITY OF...DIET AND LIFESTYLE MODIFICATIONSREFERENCES |
|---|
-TS [22,41,42], water soluble preparations of vitamin E [18,28], vitamin A and its derivatives [8,44] and ß-carotene [8,45] enhance the growth inhibitory effect of most of the currently used chemotherapeutic agents on some cancer cells. Some examples of the effect of vitamins C and E in combination with standard therapeutic agents have been summarized in Tables 4 and 5, and Fig. 2 to 4. The extent of this enhancement depends on the dose and form of vitamin, the dose and type of chemotherapeutic agent and the type of tumor cells. However, vitamin C alone failed to enhance the effect of vincristine, 6-thioguanine, 1(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), adriamycin [41], and it reduced the effect of methotrexate and 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) on neuroblastoma cells in culture [12]. A mixture of vitamins containing vitamin C failed to produce such an effect in combination with DTIC on human melanoma cells in culture [4]. A few in vivo studies support the concept that antioxidant vitamins selectively enhance the effect of standard therapy on tumor cells and thereby increase cure rates. For example, vitamin A (retinyl palmitate) or synthetic ß-carotene in combination with x-irradiation or cyclophosphamide, increased the cure rate from 0 to over 90% in rats with transplanted adenocarcinoma of the breast [8]. The purity of ß-carotene prior to administration was not reported; therefore, the above effect of ß-carotene cannot be attributed to ß-carotene alone. In contrast to the above effect, synthetic ß-carotene reduced the growth-inhibitory effect of 5-FU, but it enhanced the growth-inhibitory effect of adriamycin and an alkylating agent [45]. A thio-containing antioxidant, pyrrolidinedithiocarbamate (PDTC), and a water-soluble vitamin E analogue (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; vitamin E), enhanced antitumor effects of 5-FU and doxorubicin in vitro against several cancer cell lines, and the effect of 5-FU in vivo against two colorectal cancer cell lines [18]. Similar results were reported earlier with vitamin C and 5-FU [12], and a water soluble preparation of vitamin E and 5-FU [28] on neuroblastoma cells. 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. Most standard therapeutic agents mediate their effects, in part, by generating free radicals which damage both normal and cancer cells. Therefore, clinical oncologists fear 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 free radical damage produced by tumor therapeutic agents. The available experimental data suggest that such fear has no scientific basis. For example, vitamin C [12,13], -TS [22,41,42], water soluble preparations of vitamin E [18,28], vitamin A and retinoids [8,44] and ß-carotene [8,45] individually enhance the growth inhibitory effect of x-irradiation and certain chemotherapeutic agents on tumor cells in vitro and in vivo. Some examples are illustrated in Fig. 2 to 4. This is a direct demonstration that antioxidants do not protect cancer cells against free radical and growth-inhibitory effects of standard therapy. On the contrary, they enhance its growth-inhibitory effects on tumor cells, but protect normal cells against its adverse effects. The failure of antioxidants to protect cancer cells and the success of antioxidants in protecting normal cells against the growth-inhibitory effects of standard tumor therapeutic agents can be attributed to the following: a) cancer cells can accumulate high intracellular levels of vitamins [22] due to altered homeostatic controls for vitamin uptake, whereas normal cells cannot accumulate high levels of vitamins due to intact homeostatic controls; and b) an excessive intracellular accumulation of antioxidant vitamins affects a variety of biochemical events in cancer cells, including, inhibition of protein kinase C in tumor cells [30,31,46], reduction of the expression of c-myc and H-ras genes in tumor cells [7,32], reduction of phosphorylation and transactivation of E2F [24], enhancement of the synthesis and secretion of transforming growth factor-ß [21], and induction P21, a powerful inhibitor of the cell cycle [18]. All of these intracellular signals are considered growth-inhibitory signals for most tumor cells. Therefore, the initial protection of cancer cells from free radical damage by antioxidant vitamins becomes irrelevant because of the above subsequent intracellular events which are hypothesized to lead to growth inhibition, cell differentiation and cell death. The normal cells, which were initially protected from free radical damage by antioxidants, continued to be viable because antioxidant vitamins, presumably by virtue of their lack of intracellular accumulation, failed to influence growth inhibitory signals.
|
|
|
|
-2b produced a higher degree of growth inhibition than that caused by vitamins alone or chemotherapeutic agents alone (Table 6). It is interesting to note that vitamin C, when used individually, blocked that action of DTIC on murine neuroblastoma tumor cells in vitro [12]; however, when it is used in a mixture of antioxidant vitamins, produced no such effect on human melanoma cells in culture. On the contrary, such a mixture of vitamins enhanced the effect of DTIC on melanoma cells in vitro [4]. This observation further suggests that the use of single vitamins in the treatment of human cancer has no biological rationale.
|
|
EFFICACY OF ANTIOXIDANT VITAMINS IN COMBINATION WITH HYPERTHERMIA |
|---|
|
TOPABSTRACTINTRODUCTIONEFFICACY OF STANDARD TUMOR...EFFICACY OF EXPERIMENTAL CANCER...ANTI-CANCER PROPERTIES OF...ANTI-CANCER PROPERTIES OF...EFFICACY OF ANTIOXIDANTS IN...EFFICACY OF ANTIOXIDANT VITAMINS...ANTIOXIDANT VITAMINS IN...REDUCTION OF TOXICITY OF...DIET AND LIFESTYLE MODIFICATIONSREFERENCES |
|---|
-TS [43,47,48] enhances the effect of hyperthermia at 43°C as well as 41°C on murine melanoma [47] and murine neuroblastoma [48] cells in culture (Table 7). The mechanisms of their interaction are unknown; the effect of other antioxidants in combination with hyperthermia on the growth of tumor cells has not been studied. It is important to observe that antioxidants such as -TS can enhance the growth-inhibitory effect of hyperthermia on tumor cells in vitro. Therefore, antioxidant vitamin supplements may improve the efficacy of hyperthermia in the management of human cancer.
|
|
ANTIOXIDANT VITAMINS IN COMBINATION WITH CERTAIN BIOLOGICAL RESPONSE MODIFIERS (BUTYRIC ACID, CAMP AND INTERFERON) |
|---|
|
TOPABSTRACTINTRODUCTIONEFFICACY OF STANDARD TUMOR...EFFICACY OF EXPERIMENTAL CANCER...ANTI-CANCER PROPERTIES OF...ANTI-CANCER PROPERTIES OF...EFFICACY OF ANTIOXIDANTS IN...EFFICACY OF ANTIOXIDANT VITAMINS...ANTIOXIDANT VITAMINS IN...REDUCTION OF TOXICITY OF...DIET AND LIFESTYLE MODIFICATIONSREFERENCES |
|---|
-TS enhance the growth-inhibitory effect of butyric acid on certain tumor cells in culture. cAMP is known to induce terminal differentiation in neuroblastoma cells in culture [51]. -TS and polar carotenoids [33], originally referred to as ß-carotene [52], enhance the level of cAMP-induced differentiation in these cells [53] (Fig. 5). In addition, -TS [54] also enhances the level of cAMP-induced differentiation in murine melanoma cells in culture (Fig. 6). -TS [4] and retinoids [55] also enhance the effect of interferon in vitro and in vivo, respectively. These results suggest that antioxidant vitamins can enhance the efficacy of biological response modifiers on tumor cells. The experimental results discussed above strongly support the first part of our hypothesis: supplementation with multiple antioxidant vitamins may selectively enhance the growth-inhibitory effects of standard and experimental cancer therapies.
|
|
|
REDUCTION OF TOXICITY OF STANDARD TUMOR THERAPEUTIC AGENTS BY ANTIOXIDANT VITAMINS |
|---|
|
TOPABSTRACTINTRODUCTIONEFFICACY OF STANDARD TUMOR...EFFICACY OF EXPERIMENTAL CANCER...ANTI-CANCER PROPERTIES OF...ANTI-CANCER PROPERTIES OF...EFFICACY OF ANTIOXIDANTS IN...EFFICACY OF ANTIOXIDANT VITAMINS...ANTIOXIDANT VITAMINS IN...REDUCTION OF TOXICITY OF...DIET AND LIFESTYLE MODIFICATIONSREFERENCES |
|---|
-TS and RA reduce bleomycin-induced chromosomal breakage [69].
Based on the data discussed above and safety issues, the following vitamin supplements are recommended during and after standard therapy: Antioxidants recommended during treatment are based on the following rationale as described below. a) Multiple antioxidant vitamins including B-vitamins and appropriate minerals but without iron, copper and manganese, since these three minerals interact with vitamin C to produce free radicals. b) Additional 8 grams of vitamin C in the form of calcium ascorbate. Doses of vitamin C at 10 g or more have been used in human cancer treatment without toxicity [16]. This form of vitamin C was selected because ascorbic acid at high doses can cause upset stomach in some patients. Calcium ascorbate rather than sodium ascorbate was selected, because sodium ascorbate at high doses can increase molarity of urine in the bladder and increase the risk of chemical-induced bladder cancer in animals due to chronic irritation [70]. c) Additional 800 IU of natural vitamin E in the form of -TS. This dose was selected because it has been used in patients with melanoma for over 1 year without toxicity (Prasad and Robinson, unpublished observation). This form of vitamin E is the most potent form of vitamin E in vitro and in vivo. The natural form of vitamin E is selected, because various organs at least in rats selectively pick up the natural form of vitamin E more than the synthetic form. d) Additional natural ß-carotene 60 mg/day. The natural form of ß-carotene was selected because it has been shown to be more active. For example, natural ß-carotene protects against radiation-induced transformation in vitro, whereas synthetic ß-carotene was ineffective [36]. All vitamin doses described above should be taken orally and divided into two doses, one in the morning and one in the evening, before meals. The rationale for taking twice a day is that the biological half-life of antioxidant vitamins is about 6 to 12 hours. The above vitamin supplements should be started 48 hours prior to standard therapy and should be continued until 1 month after the completion of standard therapy. After that, doses of vitamin C, vitamin E and ß-carotene should be reduced by one-half gradually over a 4-week period. The multiple vitamins together with reduced doses of vitamin C, vitamin E and ß-carotene should be continued throughout one’s lifetime (for patients in remission).
|
DIET AND LIFESTYLE MODIFICATIONS |
|---|
|
TOPABSTRACTINTRODUCTIONEFFICACY OF STANDARD TUMOR...EFFICACY OF EXPERIMENTAL CANCER...ANTI-CANCER PROPERTIES OF...ANTI-CANCER PROPERTIES OF...EFFICACY OF ANTIOXIDANTS IN...EFFICACY OF ANTIOXIDANT VITAMINS...ANTIOXIDANT VITAMINS IN...REDUCTION OF TOXICITY OF...DIET AND LIFESTYLE MODIFICATIONSREFERENCES |
|---|
The proposed recommendations discussed above will test our hypothesis that vitamin supplements, diet, and lifestyle modifications may markedly improve the efficacy of standard and experimental therapies by enhancing their growth-inhibiting effects selectively on tumor cells, and by reducing their toxicity to normal cells. The proposed recommendation for vitamin supplements and diet and lifestyle modifications may also reduce the risk of second malignancies, which are being detected at increased rates among survivors of standard cancer treatment.
|
|
ACKNOWLEDGMENTS |
|---|
Received January 1, 1998. Accepted May 1, 1998.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONEFFICACY OF STANDARD TUMOR...EFFICACY OF EXPERIMENTAL CANCER...ANTI-CANCER PROPERTIES OF...ANTI-CANCER PROPERTIES OF...EFFICACY OF ANTIOXIDANTS IN...EFFICACY OF ANTIOXIDANT VITAMINS...ANTIOXIDANT VITAMINS IN...REDUCTION OF TOXICITY OF...DIET AND LIFESTYLE MODIFICATIONSREFERENCES |
|---|
2b on human melanoma cells in culture by a mixture of vitamins.
Nutr Cancer
22:
233–245,
1994.[Medline]
-tocopheryl hemisuccinate and cholesteryl hemisuccinate on murine leukemia cells result from the action of the intact compounds.
Cancer Res
54:
3346–3351,
1994.-tocopherol, -tocopherol polyethylene glycol 1000 succinate and -tocopherol succinate in isolated hepatocytes and liver microsomal suspensions.
Biochem Pharmacol
39:
1597–1601,
1990.[Medline]
-tocopheryl succinate.
Cancer Lett
116:
17–22,
1989.
-2a: Highly active systemic therapy for squamous cell carcinoma of the cervix.
J Natl Cancer Inst
84:
241–245,
1995.This article has been cited by other articles:
|
|
 |
|
  B. D. Lawenda, K. M. Kelly, E. J. Ladas, S. M. Sagar, A. Vickers, and J. B. Blumberg Should Supplemental Antioxidant Administration Be Avoided During Chemotherapy and Radiation Therapy? J Natl Cancer Inst, June 4, 2008; 100(11): 773 - 783. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Doyle, L. H. Kushi, T. Byers, K. S. Courneya, W. Demark-Wahnefried, B. Grant, A. McTiernan, C. L. Rock, C. Thompson, T. Gansler, et al. Nutrition and Physical Activity During and After Cancer Treatment: An American Cancer Society Guide for Informed Choices CA Cancer J Clin, November 1, 2006; 56(6): 323 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Donapaty, S. Louis, E. Horvath, J. Kun, S. M. Sebti, and M. P. Malafa RRR-{alpha}-Tocopherol succinate down-regulates oncogenic Ras signaling. Mol. Cancer Ther., February 1, 2006; 5(2): 309 - 316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Bairati, F. Meyer, M. Gelinas, A. Fortin, A. Nabid, F. Brochet, J.-P. Mercier, B. Tetu, F. Harel, B. Abdous, et al. Randomized Trial of Antioxidant Vitamins to Prevent Acute Adverse Effects of Radiation Therapy in Head and Neck Cancer Patients J. Clin. Oncol., August 20, 2005; 23(24): 5805 - 5813. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Seely, E. J. Mills, P. Wu, S. Verma, and G. H. Guyatt The Effects of Green Tea Consumption on Incidence of Breast Cancer and Recurrence of Breast Cancer: A Systematic Review and Meta-analysis Integr Cancer Ther, June 1, 2005; 4(2): 144 - 155. [Abstract] [PDF]
|
|
|
|
|
|
I. Bairati, F. Meyer, M. Gelinas, A. Fortin, A. Nabid, F. Brochet, J.-P. Mercier, B. Tetu, F. Harel, B. Masse, et al. A Randomized Trial of Antioxidant Vitamins to Prevent Second Primary Cancers in Head and Neck Cancer Patients J Natl Cancer Inst, April 6, 2005; 97(7): 481 - 488. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Gonzalez, J. R. Miranda-Massari, E. M. Mora, A. Guzman, N. H. Riordan, H. D. Riordan, J. J. Casciari, J. A. Jackson, and A. Roman-Franco Orthomolecular Oncology Review: Ascorbic Acid and Cancer 25 Years Later Integr Cancer Ther, March 1, 2005; 4(1): 32 - 44. [Abstract] [PDF]
|
|
|
|
 |
|
 A. K. Pathak, M. Bhutani, R. Guleria, S. Bal, A. Mohan, B. K. Mohanti, A. Sharma, R. Pathak, N. K. Bhardwaj, K. N. Prasad, et al. Chemotherapy Alone vs. Chemotherapy Plus High Dose Multiple Antioxidants in Patients with Advanced Non Small Cell Lung Cancer J. Am. Coll. Nutr., February 1, 2005; 24(1): 16 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. N. Prasad Multiple Dietary Antioxidants Enhance the Efficacy of Standard and Experimental Cancer Therapies and Decrease Their Toxicity Integr Cancer Ther, December 1, 2004; 3(4): 310 - 322. [Abstract] [PDF]
|
|
|
|
 |
|
 M. B. Schabath, H. B. Grossman, G. L. Delclos, L. M. Hernandez, R. S. Day, B. R. Davis, S. P. Lerner, M. R. Spitz, and X. Wu Dietary Carotenoids and Genetic Instability Modify Bladder Cancer Risk J. Nutr., December 1, 2004; 134(12): 3362 - 3369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Zeisel Antioxidants Suppress Apoptosis J. Nutr., November 1, 2004; 134(11): 3179S - 3180S. [Full Text] [PDF]
|
|
|
|
|
|
M. Gaynor One Oncologist's View of Integrative Care: Keynote Address, Comprehensive Cancer Care Conference, April 2003 Integr Cancer Ther, March 1, 2004; 3(1): 82 - 87. [PDF]
|
|
|
|
|
|
E. J. Ladas, J. S. Jacobson, D. D. Kennedy, K. Teel, A. Fleischauer, and K. M. Kelly Antioxidants and Cancer Therapy: A Systematic Review J. Clin. Oncol., February 1, 2004; 22(3): 517 - 528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. A. Norman, R. R. Butrum, E. Feldman, D. Heber, D. Nixon, M. F. Picciano, R. Rivlin, A. Simopoulos, M. J. Wargovich, E. K. Weisburger, et al. The Role of Dietary Supplements during Cancer Therapy J. Nutr., November 1, 2003; 133(11): 3794S - 3799. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Brown, T. Byers, C. Doyle, K. S. Courneya, W. Demark-Wahnefried, L. H. Kushi, A. McTiernan, C. L. Rock, N. Aziz, A. S. Bloch, et al. Nutrition and Physical Activity During and After Cancer Treatment: An American Cancer Society Guide for Informed Choices CA Cancer J Clin, September 1, 2003; 53(5): 268 - 291. [Abstract] [Full Text]
|
|
|
|
 |
|
 H. E. Seifried, S. S. McDonald, D. E. Anderson, P. Greenwald, and J. A. Milner The Antioxidant Conundrum in Cancer Cancer Res., August 1, 2003; 63(15): 4295 - 4298. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. I. Block and M. N. Mead Vitamin C in Alternative Cancer Treatment: Historical Background Integr Cancer Ther, June 1, 2003; 2(2): 147 - 154. [Abstract] [PDF]
|
|
|
|
|
|
J. A. Drisko, J. Chapman, and V. J. Hunter The Use of Antioxidants with First-Line Chemotherapy in Two Cases of Ovarian Cancer J. Am. Coll. Nutr., April 1, 2003; 22(2): 118 - 123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Pathak, N. Singh, N. Khanna, V. G. Reddy, K. N. Prasad, and V. Kochupillai Potentiation of the Effect of Paclitaxel and Carboplatin by Antioxidant Mixture on Human Lung Cancer H520 Cells J. Am. Coll. Nutr., October 1, 2002; 21(5): 416 - 421. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Kumar, M. N. Jha, W. C. Cole, J. S. Bedford, and K. N. Prasad 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., August 1, 2002; 21(4): 339 - 343. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Kumar, W. C. Cole, and K. N. Prasad Alpha Tocopheryl Succinate, Retinoic Acid and Polar Carotenoids Enhanced the Growth-Inhibitory Effect of a Cholesterol-Lowering Drug on Immortalized and Transformed Nerve Cells in Culture J. Am. Coll. Nutr., December 1, 2001; 20(6): 628 - 636. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. N. Prasad, W. C. Cole, B. Kumar, and K. C. Prasad Scientific Rationale for Using High-Dose Multiple Micronutrients as an Adjunct to Standard and Experimental Cancer Therapies J. Am. Coll. Nutr., October 1, 2001; 20(90005): 450S - 463. [Abstract] [Full Text]
|
|
|
|
|
|
J. Brown, T. Byers, K. Thompson, B. Eldridge, C. Doyle, A. M. Williams, and American Cancer Society Workgroup on Nutrition and Nutrition During and After Cancer Treatment: A Guide for Informed Choices by Cancer Survivors CA Cancer J Clin, May 1, 2001; 51(3): 153 - 181. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. M. Factor, D. Laskowska, M. R. Jensen, J. T. Woitach, N. C. Popescu, and S. S. Thorgeirsson Vitamin E reduces chromosomal damage and inhibits hepatic tumor formation in a transgenic mouse model PNAS, February 29, 2000; 97(5): 2196 - 2201. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
