General Preventive Measures
- Dietary Fat
- Total Calorie Consumption
- Vitamin E
- Dairy Products and Calcium
- High Fructose
- Diet and Supplement Studies
Besides laboratory testing, physical examination, and investigative procedures to rule out the presence of PC and other diseases, an action plan to prevent their development should be considered. These types of preventive measures are preemptive, or defensive, measures. The most apparent of these relates to what we eat and drink.
There is no doubt that what we put into our bodies relates to the health of our cells. It is obvious that food intake is associated with delights to our senses of sight, smell, and taste. However, on a survival level, food is the necessary fuel source for all the cells of the human body. The quality and quantity of the food, water, and air we put into our bodies clearly have serious ramifications. There are major parallels between human nutrition and a high-performance engine:
- The kind of fuel we add to high-performance engines
- The fuel-to-air ratios that occur within the combustion chambers
- The metabolic breakdown products resulting from internal combustion
- The wear and tear on the engine due to driving habits
- The preventive measures used to increase engine life
The human body is certainly no less of a high-performance engine than that of an airplane or car. Yet, although we appreciate the preventive maintenance that is part of the strategy of engine survival, we are inconsistent when we too often ignore the needs of our own bodies--that is, until we have signs of engine breakdown. As many of us love our cars and care for them, we must do the same with our bodies.Lycopenes and Their Critical Role in Cancer Prevention
Of all nutritional literature currently in existence relating to PC, the relationship between lycopene ingestion and the health of the prostate is the clearest. Lycopene consumption been found to decrease not only the risk of PC in multiple studies,14-16 but also the risk of BC17 and pancreatic and stomach cancer,16 as well as lung cancer18.Tomato-Based Products Are the Richest Sources of Lycopene.
In these positive studies that correlated lycopene consumption with decreased risk of PC, the lycopene sources were tomato-based products. The richest sources of lycopene in the U.S. diet are ketchup, tomato juice, and pizza sauce; these account for over 80% of the total lycopene intake of Americans.19 In one study from Athens, Greece, the authors concluded that the incidence of prostate cancer in Greece could be reduced by about 40% if the population increased the consumption of tomatoes, reduced the intake of dairy products, and substituted olive oil for other added lipids.20Lycopene Consumption Correlates with Blood and Tissue Lycopene Levels.
The correlation between increased tomato-based consumption of lycopenes and the decreased risk of PC and other cancers is also found in the laboratory, where serum levels of lycopene are correlated with lycopene intake. The same holds true in studies in which tissue levels of lycopene have been studied in prostate pathology specimens.16,17
Lycopene concentrations in the serum of healthy men are typically 0.60-1.9 nmol/mL (nanomoles per milliliter).21 Biochemically, lycopene is composed of two main chemical structures or isomers: all-trans-lycopene and cis-isomers. Tomato sauce contains primarily all-trans-lycopene (83% of total lycopene). The ingestion of tomato sauce results in substantial increases in total lycopene levels in both the serum and prostate tissue and a substantial increase in all-trans-lycopene in prostate tissue but with relatively smaller increases in the serum.22 Serum lycopene levels are predominantly composed of the cis-isomer of lycopene, which represents 58-73% of the total serum lycopene, while the all-trans-isomer composes 27-42% of the serum lycopene.21
Among 72 studies identified, 57 reported that higher tomato intake or blood lycopene levels reduced the risk of cancer at a defined anatomic site; 35 of these associations were statistically significant.23 The evidence for a benefit was strongest for cancers of the prostate, lung, and stomach. Data were also suggestive of a benefit for cancers of the pancreas, colon and rectum, esophagus, oral cavity, breast, and cervix. The relative risk (RR) was determined, comparing high tomato intake or high lycopene levels with low tomato intake or low lycopene levels. In such comparisons, about half of the RR was close to 0.6 or lower.23 In another study, the odds of contracting aggressive PC were significantly lower when plasma lycopene levels were high. Plasma lycopene levels were divided into five quintiles. The highest level, the fifth quintile, showed an odds ratio (OR) of 0.56.14 These findings add up to about a 40% reduction in risk of being diagnosed with these cancer types for those with high tomato intake or the highest plasma lycopene levels.The Proof of the Pudding Is Not in the Eating but in the Assimilation.
The proof of the pudding, in the matter of dietary issues, relates more to how we assimilate what we have eaten rather than to just a history of having eaten something. It should not be surprising then that the correlation between serum or plasma lycopene levels and a lower incidence of PC is greater than the correlation between the oral intake of lycopenes and PC incidence. In a study by Lu et al., significant reductions in PC incidence were observed with higher plasma concentrations of the following carotenoids: lycopene, OR 0.17; and zeaxanthin, OR 0.22, when comparing highest and lowest quartiles.24 This translates into about an 80% reduction in PC incidence when the highest blood levels of either lycopene or zeaxanthin are achieved.Lycopenes and Strawberries Lower Risk, Especially for Aggressive and Extra-Prostatic PC.
A dietary history of significant lycopene and/or strawberry consumption correlated with a lower risk of aggressive and extra-prostatic PC.14 The lycopene source that was found to be most significant in most epidemiologic studies was the tomato, in the form of tomato sauce, stewed tomatoes, and pizza. In one large-scale study involving 812 new cases of PC over the years 1986-1992 with matched controls, of the 46 vegetables and fruits or related products significantly associated with lower PC risk, three of the four identified were related to lycopenes--tomato sauce, tomatoes, and pizza. In this study, the combined intake of tomatoes, tomato sauce, tomato juice, and pizza (accounting for 82% of lycopene intake) was associated with a reduced risk of PC for consumption frequency greater than 10 versus less than 1.5 servings a week. Lycopene intake was also associated with a 53% reduced risk for advanced PC (Stages III and IV). The other nonlycopene product identified with significantly lower PC risk was strawberries.15
The largest relevant dietary study, a prospective study in male health professionals, found that consumption of 2-4 servings of tomato sauce a week was associated with about a 35% risk reduction of total PC and a 50% reduction of advanced (extra-prostatic) PC. Tomato sauce was by far the strongest predictor of plasma lycopene levels in this study.25 These associations persisted in analyses controlling for fruit consumption, vegetable consumption, and olive oil use and were observed separately in men of Southern European or other Caucasian ancestry.26Lycopene Inhibits Cancer Cell Growth by Gene Upregulation of Connexin 43.
Lycopene functions as a very potent antioxidant. In this regard, lycopene can trap singlet oxygen and reduce mutagenesis (gene mutations) in the Ames test. Other mechanisms of lycopene action may be operative as well. Lycopene at physiological concentrations can inhibit human cancer cell growth by interfering with growth factor receptor signaling and cell-cycle progression--specifically in PC cells--without evidence of toxic effects or apoptosis of cells.27 Studies of human and animal cells have identified connexin 43, a gene, whose expression is upregulated by lycopene and which allows direct intercellular gap junctional communication (GJC). GJC is deficient in many human tumors and its restoration or upregulation is associated with decreased proliferation.Lycopene Is Synergistic with Vitamin D, Inhibiting Tumor Cell Proliferation and Enhancing Differentiation.
The combination of low concentrations of lycopene with 1,25-dihydroxyvitamin D3 exhibits a synergistic effect on cell proliferation and differentiation and an additive effect on cell-cycle progression in the HL-60 promyelocytic leukemia cell line, suggesting some interaction at a nuclear or subcellular level.18Lycopenes Reduce Cardiovascular Risk Factors.
Lycopene levels decrease with advancing age. However, in contrast to other carotenoids, they are not found to be reduced by smoking or alcohol consumption.16,19 Lycopenes also have an inhibitory effect on cholesterol synthesis and may enhance LDL degradation. Available evidence suggests that intimal wall thickness and risk of myocardial infarction are reduced in persons with higher adipose tissue concentrations of lycopene.19Lycopene Levels May Be Associated with Decreased Insulin-like Growth Factor Levels.
The consumption of cooked tomatoes was substantially and significantly associated with reduced insulin-like growth factor-1 (IGF-1) levels, with a mean change of -31.5% for an increment of 1 serving a day. The authors concluded that the strongest known dietary risk factor for PC (lycopene deficit, as reflected in a reduced intake of cooked tomatoes) is somehow related to an important endocrine factor (IGF-1) in the cause of this disease.28 However, in another study, IGF-1 was not associated with any dietary factor studied, such as total fat, carbohydrate, protein, dairy products, tomatoes, or calcium.29Suggested Ways to Increase Lycopene Consumption and Plasma Levels.
The easiest way I have found to combine a healthy intake of lycopenes into my diet is by using marinara sauce on various foods. For example, at breakfast, an egg-white omelet containing eggplant and bell peppers (ratatouille omelet) covered with marinara sauce is a healthy source of protein, contains a substantial fiber content, and is restricted in the aount of simple carbohydrates. Stewed tomatoes can be served as a vegetable side dish with lunch or dinner.Dietary Fat Increases PC Growth Rates
There are studies that show that dietary fat increases tumor growth rates in an animal model of human PC. In a mouse model of PC involving androgen-sensitive human prostatic adenocarcinoma cells (LNCaP cells), mice fed a 40.5% fat diet had mean tumor weights more than 2 times greater than mice fed a 21% fat diet. The 40.5% fat diet approximates that found in the average American male diet, which has been determined to be 36%.30
The slower tumor growth associated with the low-fat diet occurred even after the formation of measurable tumors when the diets were changed from 40% fat to 21% fat. Serum PSA levels also were highest in the 40.5 kcal% fat group and lowest in another group fed only 2.3 kcal% fat.30Reduction of Total Calorie Consumption Decreases Tumor Size by Decreasing VEGF, Angiogenesis, and IGF-1 and by Increasing Apoptosis
The emphasis on dietary fat, per se, has lessened our focus on the importance of caloric over-consumption. Fat excess, however, is linked to excessive calorie consumption, since fat contains twice as many calories, gram for gram, as protein or carbohydrate.
I believe that diet should be regarded as having serious biochemical relevance to the health of the individual. You are, for the most part, what you eat (or at least what you assimilate). Western societies, especially the United States, are consumers of excessive calories. Excessive caloric consumption, especially coupled with a sedentary lifestyle, is a significant factor that adversely affects longevity.
An important study demonstrated that energy intake (caloric intake) modulates the growth of prostate tumors in two animal models: the androgen-dependent Dunning R3327-H adenocarcinoma in rats and the androgen-sensitive LNCaP human adenocarcinoma in severe combined immunodeficiency (SCID) mice.31 Specifically, decreasing calorie consumption (energy restriction) by 20-40% from the control animals fed ad libitum resulted in:
- Increased PC cell apoptosis (programmed cell death)
- A two- to threefold reduction in PC angiogenesis as measured by microvessel density
- A decrease in vascular endothelial growth factor (VEGF) expression
- A decrease in circulating levels of IGF-1
- A significant decrease in tumor size
Therefore, all of these findings were benefits observed in the calorie-restricted group. This study showed that the nutritional status directly or indirectly influenced interaction between tumor cells and local blood vessels by changing the expression of angiogenic growth factors. In the Dunning model, energy (calorie) restriction resulted in a striking inhibition of VEGF expression. In the LNCaP model, there was little baseline expression of VEGF. However, there was an almost threefold reduction from the baseline IGF-1 levels in blood samples from LNCaP-bearing mice that were subjected to energy restriction.IGF-1 Levels Stimulate PC Growth, Upregulate uPA, and Stimulate Angiogenesis.
Higher IGF-1 levels are associated with a fourfold greater risk of developing PC.32 IGF-1 is a known mitogen (stimulator of cell division and tumor growth) for PC. IGF-1 receptors are found on the PC cell as well as on osteoblasts.33 IGF-1 stimulates the PC cell to make uPA (urokinase-type plasminogen activator), a cell product implicated in the invasiveness and metastasis of PC. The uPA receptors are on the PC cell and on osteoblasts. IGF-1 adds further insult by also acting as an angiogenic growth factor.34
Gene expression of IGF-1 and its receptor are inhibited by 5-alpha-reductase inhibitors such as Proscar.35IGF-1 and uPA Act Together to Increase Aggressive PC Growth.
There are studies demonstrating that elevations of uPA and its receptor are associated with nonorgan-confined PC at radical prostatectomy (RP), disease progression with metastases, and a poorer overall survival.36 uPA works closely with IGF-1 and its receptors, cleaving IGF-1 from its binding proteins. uPA is also part of an autocrine pathway for the PC cell, allowing uPA to stimulate PC cell growth and make more uPA at the same time.Good News! GLA and EPA Inhibit uPA.
Of interest is the fact that uPA production is inhibited by gamma-linolenic acid (GLA) and eicosapentenoic acid (EPA).37 GLA and EPA, which are essential fatty acids, are among the important players in the prevention of disease and in maintenance of health. This is discussed by Barry Sears, Ph.D., in Omega Rx Zone.38 Sears beautifully presents the interconnection between restriction of calories, along with dietary adjustments of carbohydrate, protein, and fat intake, and the production of a class of fatty acids called eicosanoids. An understanding of these issues is fundamental to our ability to prevent disease and maintain or recapture health.
More Advantages to Caloric Restriction and Avoidance of Hyperinsulinemia. Sears stresses the importance of caloric restriction by means of limiting the intake of high-density carbohydrates such as bread, pasta, grains in most cereals, and starches such as those found in potatoes. This reduction of caloric intake by lowering high-density carbohydrate intake decreases the stimulation of the pancreas to make insulin and limits all the adverse side effects associated with increased insulin levels (hyperinsulinemia).
Caloric restriction has been shown to be an important factor in augmenting the immune system and improving longevity. Caloric restriction reduces free radical production, which if otherwise unchecked, damages DNA and oxidizes polyunsaturated fats. Caloric restriction increases levels of superoxide dismutase (SOD), glutathione, melatonin, DHEA, peroxidase, and catalase. The latter substances are important defense mechanisms in our body that are known to decrease with aging. Caloric restriction is instrumental in lowering the production of cortisol. Cortisol is associated with increased stress levels, and an imbalance in cortisol production leads to immune deficiency and bone loss through resorption, leading to osteopenia and osteoporosis, as well as muscle breakdown and aging of the skin.
Calorie restriction, as proposed by Sears and others, has been shown to also reduce advanced glycosylated end-products (AGE). These are carbohydrate-protein complexes associated with hyperinsulinemic states; they are associated with cardiovascular disease, Alzheimer's disease, kidney disease, and other degenerative states.
We need to rethink how much food we need to eat. Our ideal body weight should be taken seriously. If we were to do this alone, we would eliminate most cases of diabetes, hypertension, hypercholesterolemia, stroke, heart disease, and a significant amount of cancer from our lives and those of our loved ones. We should consume 500 calories a meal and 100 calories a snack. Modifications of this are based on the level of activity, age, and body surface area. Nutritional software and nutritional counseling should be an integral part of our approach to good health.Insulin-Stimulating Carbohydrate Is the Subcomponent of Carbohydrate That Damages.
Sears presents a very logical approach to our eating habits in relation to health and disease. If hyperinsulinemia is crucial to the development of many of our biochemical problems--from arthritis to neurodegenerative disease to cancer--then understanding the carbohydrate loads we subject our bodies to should be a major tool in maintaining good health. Sears characterizes carbohydrates by the amount of insulin-stimulating carbohydrate (ISC) that they contain. The ISC is the total carbohydrate content (in grams) minus the amount of fiber (in grams) it contains. An example he gives is 1 cup of broccoli containing a total of 7 grams of carbohydrate, of which 4 grams are fiber. The difference between the two equals the ISC content or 3 grams. Fruits and vegetables, which are high in fiber, generally have a lower ISC content than do starches, grains, and pasta. Therefore, analogous to PSA (benign-related versus cancer-related) and to cholesterol (total cholesterol versus LDL versus HDL), any intelligent discussion on carbohydrates must specify the components in question.High Density Carbohydrates Should Be Minimized.
An important variable in nutrition relates to the quantity or volume of food that we eat at each meal. Therefore, we need to specify carbohydrate intake, and in particular ISC content, as a function of ISC per unit volume of food or serving. A serving of mashed potatoes (1 cup) containing a total of 40 grams of carbohydrate, with 2 grams being fiber, would have the difference--38 grams--as ISC. The same serving of broccoli containing a total of 7 grams of carbohydrate, with 4 grams being fiber, would have 3 grams of ISC per serving. The ISC density, or ISC per unit serving, comparing mashed potatoes to broccoli is therefore 38 versus 3. Carbohydrates that deliver a high insulin-stimulating effect per unit serving are termed high-density carbohydrates. Carbohydrates that are proportionally higher in fiber and lower in ISC per unit serving are called low-density carbohydrates. In our PC analogy, PSA density would relate to carbohydrate density.Glycemic Index Further Modifies the Concept of ISC Content: The Glycemic Load.
Insulin release is also related to the rapidity of increase of the blood sugar after ingestion of carbohydrates. The concept of glycemic index is used to account for this variable. The glycemic index measures the rate of carbohydrate entry into the bloodstream. Factors relating to the glycemic index of a particular food include the following:
- The amount of fiber it contains
- The amount of fructose the carbohydrate contains relative to the amount of glucose
- The amount of fat eaten with the carbohydrate
High fiber and increased amounts of fructose (sugar from fruits) both function to lower the glycemic index. Fat consumed with carbohydrates will also mollify the glycemic effect and lower the glycemic index. Sears ties this nicely together by using the concept of glycemic load (GL): the amount of insulin-stimulating carbohydrate multiplied by the glycemic index of the carbohydrate (ISC „ GI).Volume of Food Eaten.
An additional factor that must also be accounted for is the volume of carbohydrate ingested. You might be looking intelligently at the total carbohydrate content, noting the fiber content and determining the grams of ISC. You might even be smart enough to have memorized the glycemic indices of many of the foods you eat to determine the GL. However, if you double or triple the volume of carbohydrate you eat, you can make it up in volume and still be overstimulating the production of insulin. These topics relating to balancing protein, carbohydrate, and healthy fats, are discussed in the Omega Rx Zone by Sears, as well as in his other books. I regard Sears as a front-line thinker, and his books should be required reading by patients and physicians alike.Eicosanoid Balance.
Sears emphasizes in all of his books the importance of eicosanoid balance. Eicosanoids are hormones that are made within the cell membrane of each and every cell--all 60 trillion cells in a human body. Eicosanoids are 20-carbon structures. Eicosanoids have autocrine, paracrine, and endocrine effects. That is, they affect the very cell that produces the eicosanoid (autocrine effect), as well as nearby cells (paracrine effect) and distant cells (endocrine effect). As with every aspect of biology, balance is a critical issue relating to good health as well as the development and progression of various diseases. Likewise, eicosanoid balance plays a central role that puts this desired biological endpoint at the hub of the integrative medicine wheel. Eicosanoids, and the balance of good versus bad eicosanoids, can be seen as the heart and soul, muscle, bone, and sinew, literally and figuratively, of holistic medicine.
Clearly pertinent to a discussion of PC is the fact that the first eicosanoids isolated in 1936 by Ulf von Euler were prostaglandins--eicosanoids isolated from the prostate gland. Eicosanoids are the oldest hormones, tracing their origin back 500 million years ago to production by sponges. Hormones are messengers involved in communication between cells. A hormone is formally defined as a substance, usually a peptide or steroid, produced by one tissue and conveyed by the bloodstream to another to affect physiological activity, such as growth or metabolism. All of medicine--in fact, all of life--represents issues of communication and balance. Such is the case at every level of existence. This is true for the cell, tissues, an organism, a human individual, a family, a community, a society, a nation, a planet, and the universe. If there was ever a guiding principle that is truly holistic, it is the principle of communication and balance.Arachidonic Acid Metabolites Increase PC Growth, Invasion, and Metastasis.
Eicosanoid synthesis involves the release of arachidonic acid (AA) from cell membrane phospholipids by an enzyme called phospholipase A2 (PLA2). AA then undergoes metabolism by cyclooxygenases (COXs) and lipooxygenases (LOXs). AA is an omega-6 fatty acid that is known to generate free radicals and is considered an unfavorable eicosanoid. Specific metabolites of AA, for example, PGE2 and 5-HETE, are created through the actions of the enzymes COX-2, 5-LOX, 12-LOX, and 15-LOX. These metabolites are examples of bad eicosanoids and have been implicated in PC growth and metastasis.39,40 In a study of human PC in which 5-LOX and its metabolite 5-HETE were evaluated in both malignant and benign prostate tissue within the same patient, both 5-LOX and 5-HETE were significantly overexpressed in the PC tissue.41 In other words, specific eicosanoids are modulators of tumor cell interactions with certain host components within the context of cancer growth, invasion, and spread.
The administration of PGE2 to prostate, breast, and colon cancer cells resulted in increased cellular proliferation. Some studies have shown that stimulation of PC growth is related more to COX-2 and a resultant increase in angiogenesis than to PGE2.42Inhibition of AA and Its Metabolites Causes PC Apoptosis.
Laboratory studies have shown a significant reduction in cancer cell invasiveness by inhibitors of PLA2, as well as by general COX inhibitors such as ibuprofen (Motrin) and also by specific COX-2 inhibitors.43 In this particular study, the mechanism of action was related to a reduction in angiogenesis factors called matrix metalloproteinases (MMPs). Other studies have shown a significant role for COX-2 inhibition in PC with demonstration of reduction in microvessel density of the tumor related to a decrease in VEGF, a potent angiogenesis factor.44 Apparently, within the center of PC tumors a state of lower oxygen tension exists (hypoxic center) which stimulates VEGF. COX-2 inhibition seems to be able to prevent this hypoxia-induced upregulation of VEGF and angiogenesis. An ibuprofen derivative called Flurbiprofen® inhibited PGE2 and reduced PC cell growth by inhibiting upregulation of COX-2.45
Multiple papers have shown that inhibition of 5-LOX leads to PC apoptosis.46-49EPA and DHA Lower PC Risk.
EPA, an omega-3 fatty acid, has been shown to suppress AA formation by inhibiting the enzyme delta-5-desaturase.50 Some epidemiologic studies have shown that high intakes of EPA and DHA lower PC risk substantially.51 Other studies have shown a reduction in PC risk only with a decrease in the ratio of AA to EPA (AA:EPA).52 A combination of GLA and EPA administered to humans was shown to strongly increase serum EPA and DGLA levels and to reduce AA formation and AA metabolites such as leuko-trienes.50
Foods rich in EPA include coldwater fish such as tuna, sardines, herring, swordfish, and salmon. Commercially available pharmaceutical-grade fish oils also contain large amounts of EPA and DHA.Selenium Prevents PC in Select Patients
Measures to prevent PC must be a routine part of the counsel that general practitioners and internists give their patients. Selenium
intake of at least 200 mcg a day should be a consideration in the prevention of PC throughout the world. Low plasma selenium is associated with a four- to fivefold increased risk of PC.53 In addition, levels of plasma selenium also decrease with age, resulting in middle-aged to older men being at a higher risk for low selenium levels. Ideally, baseline levels of selenium should be obtained before beginning routine selenium supplementation. It would make sense to begin such a micronutrient and mineral assessment at age 25 and perhaps every 10 years thereafter.
The studies of selenium supplementation and its role in preventing PC need continued clarification. In one study, selenium supplements provided benefit only for those individuals who had lower baseline plasma selenium levels.54 Other subjects with normal or higher levels did not benefit and had a slightly increased risk for PC. The studies by Clark et al. showed that selenium reduced the incidence of PC in men 63%.54,55 The mechanism of selenium anti-PC activity appears related to selenium's antiproliferative effect against PC. Selenium affects the cell cycle with up-regulation of cell-cycle regulators such as p21 and p27, resulting in a decrease in PC growth due to G1 arrest and up to an 80% reduction in the S-phase of PC growth.56Selenium Enhances Cell Kill with Taxol and Adriamcyin Chemotherapy.
Selenium also has been shown to have a significant antineoplastic effect on breast, lung, liver, and small intestinal tumor cells. Supplementation with selenium enhanced the chemotherapeutic effects of Taxol (paclitaxel) and Adriamycin (doxorubicin) in these cells beyond that seen when the chemotherapeutic drugs were used alone. In studies of the PC cell lines LNCaP and PC-3, the addition of Taxol or Adriamycin, in combination with selenium, caused small but significant inhibition of the PC cell growth. In the cited studies, the optimal inhibition of tumor growth occurred when the plasma selenium level was between 4 -40 ng/mL after 72 hours of treatment.57Continued
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