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 as a function of ISC per unit volume of food. 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 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 still be over-stimulating the production of insulin. These topics relating to balancing protein, carbohydrate, and healthy fats, are discussed in the Omega Rx Zone by Sears.
Eicosanoids are hormones that are made within the cell membrane of each and every cell--all 60 trillion cells in the 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 lipoxygenases (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 over-expressed 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 PGE2.42
Inhibition 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 up-regulation of VEGF and angiogenesis. An ibuprofen derivative called Flurbiprofen® inhibited PGE2 and reduced PC cell growth by inhibiting up-regulation of COX-2.45
Multiple papers have shown that inhibition of 5-LOX leads to PC apoptosis.46-49
EPA 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. 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 (see Figure 3) 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.56
Selenium 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.57
Vitamin E Isomers Alpha- and Gamma-Tocopherol plus Selenium Combine to Reduce PC Risk
A large-scale study of almost 11,000 men in Maryland showed that the protective effects of high selenium levels, and similarly that of the alpha-tocopherol isomer of vitamin E, were only observed when the concentrations of the gamma tocopherol isomer of vitamin E were also high.58 In this study, the risk of PC declined with increasing concentrations of alpha-tocopherol, with the highest concentration associated with a 68% PC risk reduction. For gamma-tocopherol, men with levels in the highest fifth of the distribution had a fivefold greater reduction in the risk of developing PC than men in the lowest fifth (p = .002). The observed interaction between alpha-tocopherol, gamma-tocopherol, and selenium suggested that combined alpha- and gamma-tocopherol supplements, used in conjunction with selenium, should be considered in future PC prevention trials.
Vitamin E Succinate Inhibits PC Cell Growth and PSA Expression
In another study, vitamin E succinate inhibited cell growth of PC cells in the LNCaP line by suppressing androgen receptor expression and PSA expression. The combination of Eulexin (flutamide) with vitamin E succinate resulted in a more significant inhibition of LNCaP cell growth.59 The same investigators demonstrated that selenomethionine also showed an inhibitory effect on LNCaP cell growth but that this appeared to be independent of androgen receptor or PSA pathways.
Vitamin E Reduces Incidence of PC in Smokers in Two Separate Studies
A study of over 29,000 male smokers in Finland, ages 50-69, disclosed a 32% decrease in the incidence of PC (95% confidence interval [CI] = -47% to -12%). This was observed among the subjects who had received 50 mg a day of alpha-tocopherol (n = 14,564) in contrast with those not receiving it (n = 14,569). Mortality from PC was 41% lower among men receiving alpha-tocopherol (95% CI = -65% to -1%). Among subjects receiving beta-carotene (n = 14,560), PC incidence was 23% higher (95% CI = -4% to 59%) and mortality was 15% higher (95% CI = -30% to 89%) compared with those not receiving it (n = 14,573). In this study, long-term supplementation with alpha-tocopherol substantially reduced PC incidence and mortality in male smokers.60
An important issue is whether this benefit of alpha-tocopherol, and possibly other tocopherols, is limited to smokers or those who have recently quit smoking. A report by Chan et al. (1999) showed significant benefit only to smokers or those recently quitting smoking in a study involving 47,780 U.S. male health professionals who received at least 100 IU of supplemental alpha-tocopherol. In this population, the risk of metastatic or fatal PC was reduced 56%. In the nonsmoking population, there were no beneficial findings of statistical significance.61 In a study on the relationship of green and yellow vegetable consumption to risk reduction in cancer development, a significant reduction was again found to occur only in smokers. The cancers studied included those of the mouth and pharynx, esophagus, stomach, liver, larynx, lung, and urinary bladder.62
Vitamin E Reduces VEGF Levels
A follow-up study involving the Finnish smokers compared VEGF levels in patients receiving alpha-tocopherol with those in the placebo group. There was an 11% reduction in VEGF levels in the alpha-tocopherol group as compared with a 10% increase in the placebo group (p = 0.03).63
Vitamin E Lessens Adverse Effects on PC Growth Due to Dietary Fat In vitro
Research studies have shown that vitamin E reduces growth rates of PCs resulting from a high fat diet. Tumor growth rates were highest in the animals fed a 40.5%-kcal fat diet (the typical American diet). Tumors in animals fed 40.5%-kcal fat plus vitamin E were the same as those fed a 21.2%- kcal fat diet (an ideal fat level).64
High Consumption of Dairy Products and Calcium Increase Risk of PC
A study in Sweden examined the relationship of dairy products, dietary calcium, phosphorus, and vitamin D with risk of total, extraprostatic, and metastatic PC. The results indicated that calcium intake was an independent predictor of PC [relative risk (RR) = 1.91] for calcium intakes of greater than or equal to 1183 mg a day versus less than 825 mg a day. This was especially the case for metastatic tumors with a RR equal to 2.64, controlling for age, family history of PC, smoking, and total energy and phosphorus intakes. The authors concluded that high consumption of dairy products was associated with a 50% increased risk of PC.65
A second study in the United States involved 1012 cases of PC among 20,885 men over an 11-year follow-up period. Men consuming greater than 2.5 servings a day of dairy products had a RR of 1.34 for PC after adjustment for baseline age, body mass index, smoking, exercise, and randomized treatment assignment in the original placebo-controlled trial. Compared with men consuming less than or equal to 150 mg calcium a day from dairy products, men consuming greater than 600 mg of calcium a day had a 32% higher risk of PC. The results support the hypothesis that dairy products and calcium are associated with a greater risk of PC.
Also noted was that at baseline men who consumed greater than 600 mg of calcium a day from skim milk had lower plasma 1,25(OH)(2)D(3) concentrations than did those consuming less than or equal to 150 mg of calcium a day (71 compared with 85 pmol/L or 30.06 pg/mL compared with 35.64 pg/mL; p = 0.005).66
The RR for the diagnosis of advanced PC was noted to be 2.97 in men with daily calcium consumption of greater than or equal to 2000 mg a day versus intakes of less than 500 mg a day.67 The same was true for the risk of metastatic PC, but with a stronger RR of 4.57. (A RR of 4.57 means a 4.57 times greater risk of contracting PC.) Calcium from food sources and from supplements independently increased risk of PC.
High Fructose Consumption Decreases Risk of PC
In the same study referenced above, high fructose intake was found to be related to a lower risk of advanced PC (multivariate RR, 0.51). Fruit intake was associated with a RR of advanced PC (RR = 0.63; 5 versus %1 serving a day), and this association was accounted for by fructose intake. Nonfruit sources of fructose similarly predicted lower risk of advanced PC.67
Boron Consumption Lowers PC Occurrence
Men who ate the greatest amount of boron were 54% less likely to develop PC compared to men who consumed the least amount of boron. This information was presented in the annual Experimental Biology Conference in Florida in 2001. The study was led by Cui et al. from the UCLA Medical Center and compared dietary patterns of 95 men with PC with those of 5720 males without cancer.67a The more boron-rich foods consumed, the greater the reduction in risk of being diagnosed with PC. Those men in the highest quartile of boron consumption had a 54% reduction in PC. Boron-rich foods include plums, grapes, prunes, avocados, and nuts such as almonds and peanuts. A serving of 100 grams of prunes (6 dried prunes) has 2-3 mg of boron and 6.1 grams of fiber.68
Diet and Supplement Studies Versus Cancer Risk: Confounding Findings Affecting Interpretation
The lifestyle characteristics of supplement users are certainly a potential bias in studies investigating the benefits versus risks of vitamins, minerals, and dietary habits. A study by Patterson et al. evaluated supplement users and found that, among men, supplement users had the characteristics detailed in Table 2.69
The health-minded nature of users of vitamins, mineral supplements, and dietary plans may well confound what we think we know about the relationship of such integrative health measures and investigations dealing with relative risks (RR) and odds ratios (OR) of diseases such as PC as well as other malignant and nonmalignant processes.