~Cancer: Should Patients Take Dietary Supplements? Part 3
The Molecular Effects of Folic Acid
Few people have ever heard the word methylation, yet this word holds the promise of unlocking the doors to understanding, preventing, and curing cancer. Although methylation is a biochemical reaction that occurs millions of times a day in every cell in the body, it has not been very well studied. Its connection to cancer is now under intense scrutiny because methylation acts as a switch to activate or deactivate cancer genes (Momparl i er et al. 2001; Sasaki et al. 2001).
Cancer is fundamentally cellular growth gone wild. It can involve any organ of the body, but the one factor cancers have in common is that they are made of wildly proliferating cells. Normal cells replicate themselves, then stop. Cancer cells race through all normal checkpoints of cellular growth without stopping, and they cease to communicate with other cells. Striking new research shows that the same pathological mechanism causes all of this strange behavior: methylation dysfunction.
Methylation research has opened up new avenues for the detection, prevention, and the eventual cure of cancer (Cairns et al. 2001; Goessl et al. 2001; Weihrauch et al. 2001). It has been repeatedly shown that methylation-deficient diets and/or exposure to chemicals deplete methylation and cause cancer (Issa et al. 1996; Chen et al. 2001; Kim et al. 2001). Both events can be prevented and, to some extent, reversed by methylation-enhancing supplements, which include folic acid, SAMe, vitamin B12, and trimethylglycine (TMG) (Wilcken et al. 1985; Loehrer et al. 1996; Kuan et al. 2002). How can a person know if his/her level of methylation is below the healthy level? Homocysteine can be used as a rough guide to methylation status (until methylation testing becomes widespread). If homocysteine levels are elevated, methylation is likely depressed (Yi et al. 2000).
DNA methylation is influenced by diet and methylation supplementation may reverse the progression of cancer in the early stages. It is not known, however, at what point cancer becomes irreversible. At this point, supplementation to enhance methylation would not be desirable inasmuch as methylation is also required for the synthesis of new cells, including cancer cells. For now, it is important to know that diet and exposure to chemicals can alter DNA methylation patterns and activate or deactivate genes involved in cancer (Fenech 2001). These alterations can be prevented, and potentially reversed, by dietary factors that enhance methylation, such as folic acid.
There are concerns that high doses of folic acid, vitamin B12, and S-adenosylmethionine (SAMe) may not be beneficial to the cancer patient until the disease is brought under control. A consensus does not exist among experts, and we must thus rely on the consistency of the published scientific data indicating that moderate supplementation with methylation-enhancing agents would appear to prolong survival. A moderate approach would involve 800 mcg of folic acid, no more than 1000 m c g of vitamin B12, with SAMe intake limited to around 800 mg daily. Some argue that only 200 mcg a day of folic acid and B12 be taken and SAMe be avoided by those with active cancer. It should be reassuring, however, that all human (and animal) studies published to date show that folic acid improves survival.
The most recent human study of folic acid and human cancer was conducted on 42 patients afflicted with head and neck squamous cell carcinoma. Doctors evaluated the cancer patient's blood levels of folic acid and homocysteine in relation to two control groups without cancer. Compared to the control groups, the folate level in the cancer patients was 38% lower and the homocysteine level was 22% higher. The differences in serum levels of folate and homocysteine might arise from tumor development and consequent metabolic alterations, or might precede and promote tumor progression. If low folate is a risk factor for head and neck cancer, it might suggest a role for folate as a novel preventive agent both in patients with precancerous lesions and in patients with treated head and neck squamous cell carcinoma at risk for regional recurrence and second primary tumors (Almandori et al. 2002).
Proponents of dietary supplemention by cancer patients argue that high-dose multiple antioxidant supplements before and during conventional or experimental therapy may improve treatment efficacy by increasing tumor response and decreasing normal tissue toxicity (Prasad et al. 1999b). The proponents point out that even when a conventional therapy has proven cure rates, there exists the possibility of developing second cancers as a result of treatment. In addition, conventional therapy also produces toxicity during treatment that can be severe enough to cause discontinuation of certain therapeutic agents. Therefore, if dietary supplements can reduce the toxicity of normal cells, and/or increase the response of tumor cells to conventional therapy, there would be a significant improvement over the current management of cancer.
Critics argue that antioxidant supplements should not be used while treating cancer patients with conventional therapy because they would protect cancer cells against free radicals that are produced by most anticancer agents (Labriola et al. 1999).
One way of approaching this dilemma is to observe the distinct differences of low-dose compared to high-dose antioxidants on cancer cells (Prasad et al. 1998; 1999b). Antioxidants such as vitamin A (and its drug analogs), vitamin E (tocopheryl succinate), vitamin C, and certain carotenoids, when used in high doses individually, have been shown to induce cell differentiation, growth inhibition, and apoptosis in rodent and human cancer cells in vitro and in vivo (Kline et al. 1995; Cole et al. 1997; Prasad et al. 1998; 1999b).
It appears that low-dose antioxidants might protect cancer cells against oxidative stress without inducing the desirable inhibitory effect (Park 1988; Cohen et al. 1995; Prasad et al. 1996). For example, vitamin C at a dose of 50 mcg/mL stimulates the growth of human parotid carcinoma cells and human leukemic cells in culture (Park 1988). Such low doses have no significant effect on the growth of other cancer cells (Prasad et al. 1996).
|A Pilot Study to Assess Effects
of Antioxidants in Combination with Carboplatin and Taxol on Tumor
Response in Humans with Non-small Lung Carcinoma
||Chemotherapy alone (17
||Chemotherapy + micronutrients
|Median number of cycles
||4 (6 cycles in 1 part)
||3 (6 cycles in 6 parts)
|*Five patients died of disease; one patient died of
|**One patient died of respiratory failure after pneumonectomy.
The second patient died of a severe chest infection, which could not
be treated with antibiotics in time because he resided in a remote
area. The third patient was lost to follow-up after the second cycle
of chemotherapy, and death reportedly occurred 4 months later at home
(Pathak et al., 2002).
One study showed that a mixture of four antioxidants (13- cis -retinoic acid, sodium ascorbate, tocopheryl succinate, and certain carotenoids) markedly inhibited the growth of human melanoma cells in culture (Prasad et al. 1994). Individually, these antioxidants had no effect on the growth of these tumor cells. Doubling the dose of one of the antioxidants (vitamin C) further reduced the growth of tumor cells in vitro (Prasad et al. 1994).
A mixture of four antioxidants was also more effective than the single antioxidant in reducing the growth of human parotid carcinoma cells in culture (Prasad et al. 1996). 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. This study 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 Taxol together with high doses of vitamin C, vitamin E, and beta-carotene was better than in patients receiving carboplatin and Taxol alone (Table 1).
High-dose antioxidants have been shown to inhibit the growth of different rodent and human cancer cells in vivo and in vitro (Cole et al. 1997; Prasad et al. 1998; 1999a; 1999b). For example, tocopheryl succinate (a form of dry vitamin E powder) induces apoptosis in human prostate cancer cells but not in normal prostate cells in vitro (Isreal et al. 2000). In addition, tocopheryl succinate has been shown to decrease accumulation of mitotic (dividing) cells in three human cancer cell lines but not in normal human fibroblasts (Jha et al. 1999). Tocopheryl succinate also induces chromosomal damage in human cervical cancer cells and in human ovarian cancer cells but not in normal human fibroblasts (Kumar et al. 2002). High doses of individual antioxidants such as vitamin A and its analogs, vitamin C, beta-carotene, and vitamin E have been used in rodents and humans without any effects on proliferating cell systems (Cameron et al. 1979; Seifter et al. 1984; Dreno et al. 1993; Garewal 1995; Lippman et al. 1995; Meyskens 1995; Schwartz 1995; Chinery et al. 1997; Malafa et al. 1999; Prasad et al. 1994; Prasad et al. 1999a), while exhibiting varying levels of antitumor activity.
Critics of antioxidant supplements point to a study demonstrating that tumor cells in vivo are more sensitive to antioxidant deficiency (vitamin A and E) than normal cells with respect to growth inhibition (Salganik et al. 1999). If tumor cells exhibit a greater sensitivity to a deficiency of antioxidant vitamins than normal cells, then it would make sense to try to temporarily induce an antioxidant deficiency in the body. The problem in trying to achieve a vitamin E or vitamin A deficiency is that this could cause damage to healthy tissues--some of which could be irreversible. It is also difficult to induce the kind of severe vitamin E deficiency in humans needed to adequately starve cancer cells of this antioxidant (additionally, a vitamin E deficiency has been correlated with an increased incidence of other cancers) (Woodson et al. 2002; Lagiou et al. 2001; Hammerer et al. 2000; Mannisto et al. 1999; Bohlke et al. 1999; Zhu et al. 1996).
It is interesting to note that antioxidant treatment for a short period (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. There is also variation on the growth inhibitory effects of antioxidants based on the time they are given in relationship to other cancer therapies. Furthermore, depending on the types of tumor cell, antioxidants may or may not show benefit. Vitamin A, for instance, induces cell differentiation in some tumor cells of epithelial origin (Sporn et al. 1983; Carter et al. 1996), whereas beta-carotene and tocopheryl succinate do not. Tocopheryl succinate and beta-carotene induce differentiation in murine melanoma cells (Prasad et al. 1982; Hazuka et al. 1990), whereas vitamins C and A do not. Vitamin C inhibits the growth of tumor cells but does not cause differentiation (Cameron et al. 1979; Prasad et al. 1979). These studies show that antioxidants do not produce similar effects on different types of cancer cells.
Depending on the type of therapy used, antioxidants may affect cancer cells in many different ways. For example, studies reveal that vitamin C, tocopheryl succinate and acetate, vitamin A (and its analogs), and certain carotenoids enhanced the growth inhibitory effect of most types of radiation and chemotherapy on some cancer cells in culture (Prasad et al. 1999b). The magnitude of this enhancement depended on the dose and form of the nutrient, the dose and type of chemotherapy agent, and the type of tumor cell. Tocopheryl succinate, for instance, induced differentiation of melanoma cells in culture.
Retinoid drugs have been successfully used in human cancer studies. Several mechanisms of action of antioxidants on cancer cells in vitro have been proposed. For example, high-dose antioxidants inhibit expression of the RAS oncogene (Amatruda et al. 1985; Prasad et al. 1990; Schwartz 1995) and the activity of protein kinase C (Mahoney et al. 1988; Gopalakrishna et al. 1995). Changes such as this are considered growth inhibitory signals for cancer cells.
These variable factors help explain why one group of scientists can say antioxidants have no effect (when looking only at short-term studies), and another group of scientists looking at the same antioxidants can claim a benefit (when looking at longer-term studies, at different dosing schedules relative to the use of other therapies, or at tumors of different origins).
Studies looking at different types of tumors show encouraging results. Tocopherol succinate, for instance, enhanced the effect of radiation treatment on neuroblastoma cells in culture, and tocopherol acetate enhanced the effect of the chemotherapy drug vincristine on neuroblastoma cells in culture. Vitamin C was shown to enhance the effect of the chemotherapy drug 5-fl o u o rouracil (5-FU) on neuroblastoma cells in culture.
There are a few in vivo (whole body) studies that support the concept that antioxidants selectively enhance the effect of conventional therapy on tumor cells by increasing tumor response. Retinyl palmitate (vitamin A) or synthetic beta-carotene at doses 10 times higher than the recommended daily allowance (RDA), in combination with radiation or the drug cyclophosphamide, increased the cure rate from 0 to more than 90% in mice with transplanted breast cancer (Seifter et al. 1984). A study using a thiol-containing antioxidant and a water-soluble vitamin E analog demonstrated the enhanced antitumor effects of the drugs 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 (Chinery et al. 1997). The combination of the vitamin A analog drug Accutane and the immune modulating drug alpha-interferon enhanced the levels of radiation-induced growth inhibition in human head and neck squamous cell carcinoma in vitro (DeLaney et al. 1996).
Opponents of cancer patients taking dietary supplements point out that the effect of individual antioxidant vitamins in combination with radiation or chemotherapy agents have not been systematically tested in human tumors in vivo . Although this is true, there are studies indicating that certain antioxidants in combination with radiation and chemotherapy may be beneficial. In one study, 18 nonrandomized patients with small cell lung cancer received multiple antioxidant treatment with chemotherapy and/or radiation. This type of lung cancer has a very poor prognosis. The median survival time was markedly enhanced, and patients tolerated chemotherapy and radiation therapy well (Jaakkola et al. 1992).
Similar observations were made in private practice settings (Lamson et al. 1999). A randomized trial with non-small cell lung carcinoma patients showed that tumor response in groups receiving chemotherapy plus multiple antioxidants was better than in groups receiving chemotherapy alone. Another study showed that beta-carotene supplementation reduced radiation- and chemotherapy-induced oral mucositis without interfering with their efficacy on tumor cells (Mills 1988). A combination of retinoic acid and interferon enhanced the effect of radiation therapy on locally advanced cervical cancer (Lippman et al. 1993). In a mouse study, a mixture of antioxidants reduced bone marrow suppression caused by radiation and immune therapies without interfering with the treatment efficacy in reducing tumor growth (Blumenthal et al. 2000).
Critics of cancer patients taking antioxidants remain troubled that many types of conventional therapies induce tumor cell death, in part, by generating excessive amounts of free radicals. Their concern is that high-dose antioxidant supplementation during standard cancer therapy could be harmful since the antioxidants might protect both normal and cancer cells against the cell-killing effects of tumor therapeutic agents (Labriola et al. 1999). This theory is contradicted by studies showing that vitamin C, tocopheryl succinate, and Accutane (vitamin A analog) enhanced the growth inhibitory effect of radiation and certain chemotherapy agents on tumor cells in culture and in vivo (Prasad et al. 1998; 1999b). This demonstrated that antioxidants do not protect cancer cells against the growth-inhibitory effect of conventional therapy and may in fact enhance the growth inhibitory effects on tumor cells.
Our review of the published scientific literature and conference reports would appear to indicate that cancer patients might derive enormous benefits by taking dietary supplements. We are troubled, however, by the knowledge that cancer is an extremely complex disease that defies simple solutions. We know that every person's cancer is different from another's and that even cancer cells within a given tumor show marked molecular differences (heterogeneity).
Cancer is unlike any other disease inasmuch as cancer cells often benefit from many of the same nutrients needed by healthy cells. Although cellular studies show that certain nutrients interfere with cancer cell propagation, these data are not yet conclusive.
We have gone to enormous lengths to present the facts so that the cancer patient can make an informed decision about using supplements. What we did not include in this chapter were comments from other cancer experts who have used high-potency supplements for decades in their practices. If we were to include comments from everyone who wanted to contribute to this article, it would have been heavily biased in favor of cancer patients using dietary supplements.
On the flip-side, we were also concerned about the power of negative bias, especially as it relates to folic acid. Some researchers do not believe a cancer patient should take folic acid, yet every published study shows cancer patients are surviving much longer when consuming folic acid supplements and have higher levels of folic acid in their blood. The same appears to be true for antioxidants.
Many experts equivocate when it comes to antioxidant supplements. They acknowledge that cell culture, animal, and human studies indicate that antioxidants would both help to inhibit cancer cell propagation and protect the body against therapeutic toxicities, malnutrition, immune dysfunction, and so forth. They are concerned, however, that antioxidants protect so well that they may interfere with apoptosis (programmed cell death) in cancer cells.
Contradicting this negative theory are the many studies showing that the tocotrienols (a potent form of vitamin E) induce significant inhibitory effects against active cancer cell lines. The tocotrienols may be nature's most powerful natural antioxidant, yet when certain types of cancer cells are exposed to them, a direct antiproliferative effect occurs.
To give you an idea of the debate that goes back and forth, one only has to look at studies on alpha tocopheryl succinate (dry-powder vitamin E). Some argue against taking antioxidants during radiation therapy because radiation kills cancer cells by generating massive free radicals. Yet the most recent study on this subject showed that tocopheryl succinate enhanced radiation damage to ovarian and cervical cancer cells but protected healthy cells! This study showed that both cancer and normal cells absorbed a similar amount of tocopheryl succinate, but only the cancer cells were sensitized to the radiation by this form of vitamin E. The doctors who conducted this study concluded that: "The use of alpha tocopheryl succinate during radiation therapy may improve the efficacy of radiation therapy by enhancing tumor response and decreasing some of the toxicities on normal cells" (Kumar et al. 2002).
A serious side effect from cancer radiation therapy is fibrosis to healthy tissues. Fibrosis is an inflammatory condition that causes progressive scarring (necrosis) to healthy tissue that can lead to debility or death. Antioxidants have not only been shown to prevent fibrosis, but also reverse it. Based on the published research, it would appear that patients undergoing radiation procedures might derive therapeutic and protective benefits if they consumed the proper antioxidants before, during, and after therapy. The downside, critics argue, is that long-term survival studies of radiation patients supplementing with high doses of antioxidants are lacking (Letur-Konirsch et al. 2002).
The individual stricken with cancer today needs a definitive answer about what dietary supplements are appropriate, when and how much should be taken, or whether they should be taken at all. The Life Extension Foundation is determined to make definitive recommendations but cannot make a generalized conclusive statement that accurately pertains to the use of every dietary supplement in every type of cancer during every conventional therapy. In other words, there is inadequate substantiation to address how every single supplement might affect each individual cancer patient. The evidence presented, however, speaks for itself.
The most comprehensive report dealing with this subject was published in the October 2001 issue of the Journal of the American College of Nutrition . Below is an excerpt from this paper entitled "Scientific Rationale for Using High-Dose Multiple Micronutrients as an Adjunct to Standard and Experimental Cancer Therapies" (Prasad et al. 2001):
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.
In the Cancer Adjuvant Therapy protocol, a plethora of research strongly suggests that the proper dietary supplements are of considerable value. This protocol also provides specific recommendations of dietary supplements that a cancer patient may consider.
The Cancer Chemotherapy and Cancer Radiation Therapy protocols present specific information relating to the positive and potentially negative effects of dietary supplements being used during these therapies.
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