Intervention studies using Se as a single chemopreventive agent include the Qidong trials in China, where selenite significantly reduced primary liver cancer (Yu et al. 1997). In the Nutritional Prevention of Cancer (NPC) trial in the US, 200 µg Se/d (as yeast) reduced total cancer mortality by 41%, total cancer incidence by 25% and prostate cancer incidence by 52% in a cohort of 1,300 people. The effect on total cancer was limited to male smokers (current or previous) with baseline Se levels below 113 µg/l, although non-smoking males below this level are likely to have benefited from Se supplementation in terms of prostate and colon cancer protection (Duffield-Lillico et al. 2002).
Findings in several other Se anti-cancer studies (in brief) include:
- A study of 34,000 men found that men with low baseline Se levels were three times more likely to develop advanced prostate cancer than men with high Se levels (Yoshizawa et al, 1998).
- Women who are born with mutations of the BRCA1 gene have a high risk of breast and ovarian cancer. Se supplementation for 1-3 months reduced chromosome breaks in these women to normal levels (Kowalska et al, 2005).
- A combined analysis of three randomised trials in the US found that individuals whose blood Se values were in the highest 25% had a 30% lower risk of developing bowel cancer (Jacobs et al, 2004).
- Selenomethionine caused a 50% reduction in prostate cancer, breast cancer and melanoma cells. A dose 1,000 times higher was required to inhibit normal cell growth (Redman et al, 1998).
- In a study of male smokers in Finland, those who entered the trial early (when Se levels were quite low) and had blood Se levels in the lowest quarter had a five-fold higher risk of lung cancer than those men in the highest quarter of blood Se level (Hartman et al, 2002).
- The review of Combs & Gray (1998) reported that two-thirds of the animal studies on the relationship of tumour incidence to Se status showed significant reductions by Se in the tumour incidence, with half of the studies showing reductions of 50% or more.
The NPC trial was conducted in a region of the US where Se intakes are estimated to be around 90 µg/d, well above the level required for optimal selenoenzyme activity. This suggests additional mechanisms in Se’s cancer-preventive role. While some cancer protection, particularly that through antioxidant activity, involves selenoenzymes, the anti-cancer effects of Se are likely to involve the production of specific anti-tumorigenic metabolites, such as methylselenol. Studies have suggested that Se provided in certain forms can neutralise carcinogens (e.g.cadmium), reduce DNA damage, enhance the immune system, alter gene (including p53) expression, inhibit tumour cell metabolism and neo-angiogenesis (blood vessel development around tumours), and promote apoptosis (programmed cell death) (Ip et al. 1991; Harrison et al. 1997; Combs & Gray, 1998; Jiang et al. 1999; Combs, 2000, 2001; Lu, 2000; Rayman, 2000; El Bayoumy, 2001; Finley & Davis, 2001; Seo et al. 2002).
To elaborate further on several of the proposed mechanisms of Se’s anti-cancer activity we will look at reduction of DNA damage, enhancing immunocompetence, and inhibition of angiogenesis.
DNA damage
Following exposure to oxidative stress, a cell either dies or repairs the damage. However, if the damage persists, the cell will enter a state of genetic instability that can lead to chronic diseases, including cancer (Garewal, 1997). Deficiency of various vitamins and minerals appears to mimic radiation in damaging DNA by causing single- and double-strand breaks, oxidative lesions, or both. Remedying micronutrient deficiencies is likely to lead to a major improvement in health and an increase in longevity at relatively low cost (Ames, 1998). Se has been shown to inhibit oxidative damage to lipids, proteins and DNA in numerous in vitro (Wang et al, 2004), animal (El-Bayoumy, 2001; Waters et al, 2005) and recent human studies (Kowalska et al, 2005). Further human studies are currently assessing this as well.
Immunity
Since the immunity of cancer patients is reduced and Se has been shown to stimulate immunocompetence, it is logical to conclude that Se could reduce tumours by this approach. Two intervention studies using the same Se intake (200 µg/l) used in the NPC trial improved immunity (Kiremidjian-Schumacher et al, 1994; Taylor, 1995). Se increased the expression of the high-affinity interleukin 2 receptor, which resulted in an increased ability to produce cytotoxic lymphocytes and macrophages that destroy tumour cells (Kiremidjian-Schumacher et al, 1996). [Link to Se & Immunity page]
Anti-angiogenesis
Angiogenesis refers to the process by which new blood vessels are formed within the body. For example, when tissues need more oxygen they release molecules that encourage blood vessels to grow. The ability to inhibit angiogenesis and turn off the blood supply to tumours could potentially lead to a new generation of cancer therapies. Selenium deficiency increases angiogenesis by inducing the production of vascular endothelial growth factor (VEGF), which is necessary for tumours to metastasise (spread throughout the body) (Streicher et al, 2004). Increased intake of Selenium can reduce tumour micro-blood vessel density and inhibit the expression of VEGF (Lu & Jiang, 2001). It appears that the selenoprotein, thioredoxin reductase (which regulates intracellular redox balance) has an important influence on VEGF activity (Streicher et al, 2004).
http://www.gene.com/gene/research/focusareas/oncology/angiogenesis.jsp
Higher selenium intakes needed for optimal cancer prevention
According to this two-stage model of cancer prevention, which involves Se intakes that correct nutritional deficiency as well as much higher, supranutritional intakes, individuals with nutritionally adequate Se intakes may benefit from Se supplementation (Combs & Gray, 1998). Combs (2001) suggests that the level of dietary intake required to achieve the plasma Se level of 120 µg/l, above which no anti-cancer benefit from Se was apparent in the NPC trial would be a plausible target at which to aim in order to minimise cancer risk. [Link to How much Se do we need? page] . Se’s strongest cancer preventive effect in humans appears to be for prostate cancer [Link to Prostate Cancer page], followed by colo-rectal (bowel) cancer [Link to Bowel Cancer page]. There is also evidence of Se effects against breast cancer [Link to Breast Cancer page] and lung cancer [Link to Lung Cancer page]. Se’s anti-cancer activities remain under intensive study worldwide.
Sex differences in the anti-cancer effects of selenium
Cancer risk in men has been shown in a number of studies to be more profoundly influenced by Se status than in women. Factors contributing to the apparent difference in the effects of Se on cancer incidence in men and women may include sex-based differences in the metabolism and/or tissue distribution of Se, as well as sex-related factors that influence tumour biology (Waters et al, 2004). For example, the inverse association between toenail Se concentration and smoking is stronger in men than in women (van den Brandt, 1993), and in a large US survey, alcohol consumption was positively associated with serum Se in women, but not in men ((Kafai & Ganji, 2003). Moreover, this sex effect may apply to other minerals/nutrients/antioxidants as well. A European intervention study conducted for nearly 8 years found a daily supplement comprising 120 mg vitamin C, 30 mg vitamin E, 6 mg beta-carotene, 20 mg zinc and 100 µg Se reduced total cancer incidence and all-cause mortality in men but not in women (Hercberg et al, 2004). [Link to How much Se do we need? page]
Numerous studies have found that Se and other antioxidants and phytochemicals have the effects of both enhancing the anti-cancer action of chemotherapy and radiotherapy and reducing the damage caused by these therapies to normal cells. Several of these studies are listed below:
· The methylselenol precursor methylseleninic acid (MSeA) increased the prostate cancer-killing effect of the chemotherapy drugs SN38, etoposide and paclitaxel by several times higher than the expected sum of the apoptosis induced by MSeA and each drug alone, in vitro (Hu et al, 2005).
· Treatment of Adriamycin-resistant lung cancer cells with relatively low doses of Se (as selenite) resulted in massive apoptosis (Jonsson-Videsater et al, 2004). Se supplementation of patients with small cell lung cancer which no longer responds to chemotherapy may result in improvement in survival.
· Se was found to have a significant anti-cancer effect on breast, lung, liver and small intestinal tumour cells. Supplementation of Se enhanced the chemotherapeutic effect of Taxol and Adriamycin in these cells beyond that seen with the drugs used alone. The authors stated: “These in vitro studies on several cancer cell lines suggest a potential benefit of Se-enhancement of anticancer effects of chemotherapy drugs, and therefore offer further relevance to clinical trial efforts.” (Vadgama et al, 2000).
· The chemotherapeutic drug cisplatin often causes some nephrotoxicity and hearing loss. In a randomised, placebo-controlled study, co-administration of a supplement containing vitamin C, vitamin E and selenium significantly reduced loss of high-tone hearing (Weijl et al, 2004).
· A Polish study of 31 women undergoing chemotherapy (Protecton Zellactiv) for ovarian cancer were supplemented with 200 µg Se/day for 3 months. The Se resulted in less hair loss, less abdominal pain, better appetite, and an increase in white blood cells (Sieja & Talerczyk, 2004).
· A laboratory study found that both androgen-dependent and androgen-independent prostate cancer cells that were pre-treated with Se (as sodium selenite) showed increased sensitivity to gamma-irradiation. Prostate cancer cells were more sensitive to Se-induced apoptosis than normal prostate cells (Husbeck et al, 2005).
· Treatment with selenite reduced lymphoedema (of the arm or head/neck region) caused by radiation therapy alone or by irradiation after surgery (Micke et al, 2003).
It is becoming apparent that the outcome, in terms of patient survival and general well-being, of chemotherapy and radiotherapy for a wide range of cancers would be improved by concurrent (adjuvant) treatment with a range of minerals/nutrients/antioxidants/phytochemicals/herbs. These include Se, vitamin E, vitamin C, green tea polyphenols, soy polyphenols, phytate, coenzyme Q10, alpha-lipoic acid, beta-glucan, curcumin and quercetin.
Definitions
Metastasis: spreading of cancer cells from a primary tumour to distant tissues, usually via the blood system.
p53: a gene that normally inhibits the growth of tumours. This gene is altered in many types of cancer, so mutations of p53 are considered to be a cause of some cancers.
Angiogenesis: the establishment and development of blood vessels around tumours.
Apoptosis: programmed cell death, which is desirable for the host organism in the case of cancer cells or pre-cancer cells.
Tyrosine kinase: an enzyme involved in communication within cells. Or signalling pathways.
Interleukin: a cytokine that stimulates the growth and maturation of cells of the immune system.
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