Selenium

The role of selenium in cancer prevention and as an adjunct in chemotherapy

Abstract

Selenium is an essential trace element. It is found predominantly in the form of selenoproteins and it is used in the body within the immune system, metabolism, growth and defence. The most notable role of selenium is its part of glutathione peroxidase. Although the average dietary intake for selenium varies throughout the world, it has been shown that supranutritional levels (state levels) can provide a level of chemprevention against certain types of cancers. Further research has been carried out investigating the effect of using selenium as an adjunct to chemotherapy, with an emphasis on platinum-based drugs.

1. Introduction

The human body requires many elements to function correctly. While some elements are required in large quantities, others, such as selenium, are only required in trace amounts. Since its discovery Selenium has proven to be a highly important and interesting element. Not only is it vital within the human body to help and maintain its functions (immune system, thyroid gland, metabolism, growth and defence of the body), but it has also been found to reduce the incidence of some types of cancer when taken at supranutritional levels. The form required for the most effective chemopreventive action is still under investigation, as it the effect of selenium against different forms of cancer.

Based on information that selenium exhibits some anticarcinogenic activity at high enough levels, research has been carried out investigating the effects of selenium as an adjunct in chemotherapy. Researching this is vital as many cancer patients take multivitamin and mineral supplements and other non-prescribed remedies during their treatment. Therefore, an understanding of the effects of taking these supplements during treatment for cancer is essential in ensuring that there is no negative effect on the selectivity or efficiency of the drugs. Selenium is just one of the elements taken as a supplement which has been investigated.

Chemotherapy treatments are not very specific and damage a lot of healthy cells as well as cancer cells. Many methods have been investigated to try and increase the selectivity of cancer drugs as this would result in fewer side effects for the patient. There is some evidence to suggest that taking selenium supplements during treatment can reduce the toxicity of some platinum-based drugs, without reducing the efficiency. A review of the available research carried out is detailed below.

2. Selenium

2.1 The origins and importance of Selenium

Selenium is an essential trace element in the body, and its importance has been researched in relation to disease prevention, including cancer. Selenium, which belongs to the sulphur family of elements, was first discovered by Jons Jakobs Berzelius in 1817. Up until the 1950's it was thought that Selenium was toxic to humans, but in 1958 Schwarz and Foltz (1) discovered the relationship between selenium intake via food and the prevention of liver necrosis in rats. This was the starting point for further research into the role of selenium in disease prevention. The importance of selenium in humans was realised in the 1970's when a cardiomyopathy epidemic (known as Keshan disease) in parts of China was linked to poor Selenium content in the soil, and thus in the food, which led to Selenium deficiency in many people. (2) (3)

Selenium is found in the body as part of selenoproteins, of which there are about 30 different known proteins. (2) In animal and human tissue, selenium is found mainly as L-selenomethionine or L-selenocysteine, however it should be noted that only a small percentage of L-methionine is found in the L-selenomethionine form. (2) The selenoproteins have a variety of roles within the human cells, some of which are summarised in Table 1, however in cells the role of selenium is mostly associated with oxidative metabolism. (3) It has been shown that the glutathione peroxidises, and possibly selenoproteins P and W exhibit antioxidant properties. These antioxidant proteins reduce the “potentially damaging reactive oxygen species (ROS) such as hydrogen peroxide and lipid hydroperoxides, to harmless products by coupling their reduction with oxidation of glutathione.” (2) Glutathione peroxidise uses selenium as part of a catalytic cycle, where it provides some antioxidant protection by removing oxygen from peroxides, reducing the redox potential. This type of reaction occurs in liquid media (i.e. not in the membrane) and is aided by vitamin E (which is lipid soluble). (3)

As shown in Table 1, selenium has many functions within the body, however, its role in human metabolism is obscure. It has a “metabolic relationship with tocopherols” and is associated with -SH groups in proteins. Tocopherols, like Selenium, are believed to be an antioxidant and they are thought to “help to maintain cellular stability by inhibiting oxidation of lipids in cell membranes”. (4)

Selenium deficiency is rare; however, it has been linked to an increased risk of carcinogenesis as well as Keshan disease and Kashin-Beck syndromes (which cause muscular problems). (5) Therefore, it is evident that selenium has a vital role in human health, and warranted further study.

Table 1 - Known selenoproteins and selenoenzymes and their functions (3)

Selenoprotein

Function

Glutathione peroxidises , GPx, (GPx1, GPx2, GPx3 and GPx4)

Antioxidant enzymes: remove hydrogen peroxide, lipid and phospholipid peroxides (thereby maintaining membrane integrity, modulating eicosanoid synthesis, reducing inflammation and the likelihood of propagation of further oxidative damage to biomolecules such as lipids, lipoproteins and DNA).

(Sperm) mitochondrial capsule selenoprotein

Form of glutathione peroxidase (PHGPx): shields developing sperm cells from oxidative damage and later polymerises into a structural protein required for stability/motility of mature sperm.

Iodothyronine deiodinases

Production of active thyroid hormone T3, from thyroxine, T4.

Selenophosphate synthetase, SPS2

Required for the biosynthesis of selenophosphate, the precursor of selenocysteine, and therefore for Selenoprotein synthesis

Selenoprotein P

Found in plasma and associated with endothelial cells against damage from peroxynitrate.

Selenoprotein W

Needed for muscle function.

Prostate epithelial selenoprotein (15kDa)

Found in epithelial cells of the ventral prostate. Seems to have a redox function (resembles PHGPx).

DNA-bound spermatid selenoprotein (34kDa)

Glutathione peroxidise-like activity. Found in stomach and in nuclei of spermatozoa. May protect developing sperm.

18kDa selenoprotein

Important selenoprotein found in kidney and large number of other tissues.
2.2 Sources of Selenium

Humans obtain selenium in several forms from plans, animals and seafood. The levels of selenium within these sources vary via geographical area, due to variations in the levels of selenium in the soil and its availability to the plants. (2) However, the average nutritional intake of selenium was found to be 50-350µg per day. (5) The amount of selenium humans required is dependant of many factors, and are summarised in Table 2.

Table 2 - Adequate intake (AI) and tolerable upper levels (TUL) for selenium based on the recommendations of the “Food and Nutrition Board of the Institute of Medicine of the National Academy of Sciences (2)

Adequate Intake (µg per day)

Tolerable Upper Limit (µg per day)

Infants

0-6 months

15

45

7-12 months

20

60

Children

RDA

1-3 years

20

90

4-8 years

30

150

9-13 years

40

280

Adolescents

14-18 years

55

400

Adults

19 years and older

55

400

Pregnancy

60

400

Lactation

70

400

Selenium is found predominantly as a one of various metallic selenides that are associated with sulphide ores. However, in soils it can also be found as basic ferric selenite and calcium selenate. (4) Soil concentrations vary worldwide and have been found within a wide range (from 0.1 to 1000 mg/kg), while the levels in drinking water rarely exceed 10 µg/l. (4) (delete?)

Selenium present in soil gets taken up by plants and becomes part of the plant proteins, predominantly in the form of amino acids (“L-selenocysteine and L-selenomethionine”), however, some inorganic selenium is also present. (2) Therefore, humans get selenium from the food we eat, which in turn got the selenium from soil. (delete?)

Research has shown that the selenium in food sources is found in the forms of selenate, selenocysteine, selenomethionine and selenium-methylselenocysteine, which humans ingest as grains, yeast, meat and vegetables. (2) (5)

2.3 Selenium supplementation

While the daily intake level of selenium varies worldwide, the majority of people ingest adequate levels. However, as selenium deficiency can cause health problems, some area use selenium-supplementation to ensure that the local population receives an adequate intake. For example Finland has added selenium to food (by using selenated-supplemented fertilisers) since 1984 and in northern central China the soil is treated with selenate. (3) (6)

As selenium has a role in cancer prevention (see section 3), it is vital to have an understanding of the interactions of selenium within the body and with chemotherapeutic drugs. A study carried out over 14 European countries discovered that out of the 956 cancer patients studied, 35.9% were using some form of complimentary or alternative medicine (the range between countries varied from 14.8 to 73.1%). (7) These complementary and alternative medicines covered a range of remedies, from vitamins and minerals (including selenium) to medicinal teas. Due to the large numbers of cancer patients taking supplements, it is important that the effect of these supplements is explored to ensure that they will not cause harm to the patient or interfere with chemotherapy treatment.

2.4 Summary

Is a summary needed for this section?

Garlic and nuts - higher sources of selenium

3. Use of selenium in cancer prevention

Shamberger and Frost (8) were the first to identify the relationship between cancer prevention and selenium levels in 1969, observing that the rate of cancer mortality (from any form of cancer) in the USA was inversely proportional to the areas which had a higher level of selenium in forage crops. Based on the evidence obtained from geographical studies that there was a relationship between the cancer incidence and the intake selenium within the studied populations, further research was carried out both on animals and on humans to investigate the relationship further.

3.1 Epidemiological Studies

There have been numerous epidemiological studies carried out worldwide. Following the initial study in 1969, two years later Shamberger and Wallis (9) found that mortality due to lymphomas and cancers of the gastrointestinal tract, peritoneum, lung, and breast to be lower for men and women residing in areas of the US that have either moderate or high concentration of Se in forage crops than for those residing in low-forage Se areas. (8) This was then reaffirmed by a 27-country comparison conducted by Schrauzer et al. (10) in 1977 which included “a total cancer mortality rate and age corrected mortality due to leukaemia and cancers of the colon, rectum, breast, ovary, and lung varied inversely with estimated per capita Se intake.” This was further backed up by Clark et a. (9) in 1981.

The studies progressed to look at the relationship between plasma Selenium levels, urine levels and levels found in toenails to cancer incidence, most of which reported positive data. (11) (more detail?/delete?)

3.2 Selenium and tumours in small animals

There have been over 100 investigations into the relationship of selenium and cancer incidence in animals. Although the relationship wasn't properly investigated until the early 1970's, there was some evidence which was presented in 1949 to suggest that the addition of selenium to the diets (via an azo dye) of rats reduced the number of tumours observed. (ref Clayton and Bauman) However, the results were overlooked as at this stage as selenium was still believed to be toxic.

Once it was established that selenium is an essential element, several studies were carried out investigating the relationship between various cancers and selenium. A review by Milner et al. (Milner, 1985, Whanger 1992) concluded that two-thirds of the studies showed a significant reduction in the number of tumours observed (in half of the studies, reductions of 50% or greater were observed when selenium levels were higher than the controls). (11)

However, it should be noted that an inorganic salt (Na2SeO3) or selenite were the most commonly used sources of selenium in many of the animal studies performed, and therefore further research is required to determine how the findings obtained represent the organo-selenium compounds found in food. (9) Furthermore, more recent studies have shown that there are more effective forms of selenium.

In general, the results obtained from animal and epidemiological studies indicated that there was a relationship between levels of selenium and cancer incidence, and based on these findings, trials on humans were warranted. (Move to start of section 3.3?)

3.3 Clinical Trials

There have been several studies investigating the Selenium as a way of preventing cancer. By 2004, there had been 8 trials, of which all but one showed that the selenium supplementation had a positive effect and reduced total cancer incidence. (11) From these studies, it was observed that on average, cancer patients tend to have a slightly lower level of selenium than the healthy patient controls. (9) For example, Clark et al. (ref) carried out a study over a decade and found that the selenium status and cancer incidence in the group being studied showed that the “selenium concentration was inversely related to subsequent risks of both non-melanoma skin cancer and colonic adenomatous polyps” and that patients with “plasma selenium levels less than the population median (128 ng/ml) were four times more likely to have one or more adenomatous polyps”. (9) (12)

While many studies have claimed to find a link between selenium status in serum and cancer prevention, there have been at least two studies which found no significant link. Coates et al. (ref) studied the incidence of total cancers, while Glattre et al. (ref) investigated cancers of the “bladder, colon-rectum, lung and stomach”. (9) In both cases no significant relationship was noted. Plasma levels are not the most reliable way to determine the relationship between selenium and cancer prevention, as the level in the plasma does not necessarily represent the level of biologically active selenium.

Several clinical trials have been undertaken to determine the efficacy of Selenium as a cancer preventative agent. For example, there have been three clinical investigations in China which supported the idea of Selenium as a cancer preventative agent. The first study used a daily supplement of Selenium in the form of Selenium-enriched yeast (200mg Se per day), and the results indicated that the Selenium treatment “eliminated liver cancer incidence among hepatitis surface-antigen carriers" and reduced the incidence of cancer over a two year period. The second study was carried out by adding 15ppm Selenium (as Na2SeO3) to salt. The results showed a drop in the incidence of liver cancer from 54.8 per 100,000 people to 34.5 per 100,000 people between 1984 and 1990, while the control group remained at 54-65 people per 100,000. The third study looked at an area (Henan Province, China) where high incidence of esophageal cancer had been reported. A treatment containing 50 mg Selenium per day (taken as Se-enriched yeast) along with β-carotene and vitamin E, resulted in some level of protection against total cancer mortality in the general population, however no effect was observed on subjects considered high risk (patients with esophageal dysplasia). (9) plus other references (Blot et al., 1993). Li et al., 1993

A further study was carried out in 1996 by Clark et al. (ref) which looked at the efficacy of Selenium in prevention of cancer using a group of 1312 elder Americans (mainly men). The trial took place over a decade and was a “double-blind, placebo-controlled” trial. Each subject within the group had a history of “basal and/or squamous cell carcinomas of the skin”. Daily oral supplement of 200 µg of Selenium per day (the average intake in the USA is approximately 100 µg), via Selenium-enriched yeast, was given for a mean of 4.5 years. The results are summarised in Table 3, however, as can be seen, the Selenium had failed to reduce the risk of recurrent skin cancers, however, a lower incendence of “total non-skin cancer, total non-skin carcinomas, cancers of the lung, colon-rectum, and prostate, and overall cancer mortality rate” was observed. (9) (13) (ref Clark paper)

Table 3 -Incidence in Selenium and Placebo treated subjects (ref Clark, 1996)

Site

Selenium

Placebo

Relative risk

P value

Skin carcinomas

Basal cell

377

350

1.10

0.20

Squamous cell

218

190

1.14

0.15

Lung

17

31

0.54

0.08

Prostate

13

35

0.37

0.002

Colorectal

8

19

0.36

0.025

Total carcinomas other than skin1

59

104

0.55

<0.001

Total noncarcinomas

19

16

1.17

0.65

Total cancer

77

119

0.63

0.001

1 No significant differences were detected between treatments from cancer of the head and neck, bladder, oesophagus, or breast. None of these accounted from more than 14 cancers in both treatment groups.

These human clinical trials, and previous animal studies, support that it is plausible that a link exists between selenium levels and the risk of cancer. (9) Furthermore, based on the Clark et al. (ref) study, the National Cancer Institute (NCI) launched the “Selenium and Vitamin E Chemoprevention Trial (SELECT) in 2001, which was designed to be a 12 year trial to assess the effect of selenium and vitamin E (both individually and as a combination) on the incidence of prostate cancer. In October 2008, the patients stopped receiving supplements due to inadequate evidence that vitamin E and selenium (as a combination or alone) provided protection against prostate cancer. However the health of the patients involved will be monitored for three years to give an indication of the long term effects, and the results will be released following the end of the trial. A further trial (PRECISE - Prevention of Cancer by Intervention with Selenium) with 42000 subjects is still underway, and as such the results have yet to be reported.

3.4 Metabolism pathway of Selenium

Once it was established that there was some evidence to suggest that Selenium had some efficacy in the prevention of some types of cancer, the next step was to research the mechanism by which selenium worked. Although many journals refer to the effects of selenium on various cancers, it should be noted that there are many forms of selenium, and the bioavailability of selenium is dependent on the chemical form, which in turn controls where in the body the selenium is found. For example, there is more selenomethionine found within tissue proteins compared to inorganic selenium or selenocysteine, however selenomethionine is not the most available form for use in chemoprevention. (2)

A metabolism pathway (Figure 1) for selenium has been constructed based on investigations into each selenium compound found within the body in order to gain a better understanding of which form is best for chemoprevention.

It has been documented that “selenoproteins are enzymatically digested in the small intestine to yield amino acids, oligopeptides, L-selenomethionine and L-selenocysteine”. (2) Once absorbed via the small intestine, L-selenomethionine is extracted in the liver (by hepatocytes), while the rest is circulated to other tissue. L-selenomethionine then follows the pathway of L-methionine (transsulfuration pathway) and participates in the formation of proteins. L-selenocysteine follows a different path that L-cysteine as it is “converted to hydrogen selenide (H2Se) via the enzyme selenocysteine β-lyase”. (2) As can be seen in Figure 1, there are different routes available to H2Se; it can become methylated (normally found in urine) or it can form selenophosphate (the precursor for L-selenocysteine). (ref 18 (2))

Inorganic selenium (e.g. selenite and selenate) are absorbed in the gastrointestinal tract, and are transported to the liver where some is extracted by hepatocytes while the remainder is circulated to other cells. Once the inorganic selenium is in cells, it is converted to H2Se, the uses of which have already been discussed.

3.5 Dose and form of selenium required for chemopreventive action

There are many forms of selenium within the body, as can be seen from the metabolism pathway (Figure 1), and it is thought that the chemical transformation of selenium is an important step in the chemopreventive action of selenium. Many different selenium compounds have been used in trials, on humans and animals, in order to determine the most active form for cancer prevention.

Selenomethionine (SeMet), which is found predominantly in enriched yeasts and cereal grains, and Se-methylselenocysteine (SeMCYS) (major seleno-compound in plants, garlic and broccoli) can both be metabolised by animals. (ref) As a result of this research, for several of the human studied carried out, Selenium-enriched yeasts have been used. (11) However, in “mammary-tumour model, Se-methylselenocysteine (SeMCYS) has been shown to be the most effective seleno-compound identified so far for the reduction of mammary tumours”, however, this does not mean that it will be the most effective form against other forms of cancer. (11)

The SELECT trial (ref) chose selenomethionine, CH3-Se-CH2-CH2-CH(NH2)-COOH, (Figure 2) as the source of selenium, while Methylselenocyseine (MSC) (Figure 2), a lower homolog of selenomethionine, was used to determine whether the conversion of selenium to mono-methlyated form was required for the chemopreventative action of selenium. (13) It was found that MSC doubled the mammary tumorigenesis suppression in rodents compared to selenomethionine (ref 4 from IpC02). “For example, at a level of 2 ppm Se in the diet (or 2μg Se/g diet), MSC consistently produces a 50% decrease in tumor formation, whereas the same dose of selenomethionine produces only a 20% inhibition or less.” (13) (delete?)

In addition, there is evidence suggesting that methylselenol, CH3SeH (Figure 2), is a highly important metabolite involved in selenium chemoprevention. (ref 5 from IpC02) However, problems were encountered when trying to investigate methylselenol due to its high reactivity. Therefore, MSC was used as a precursor, which underwent cleavage by β-lyase (an enzyme found in the kidneys, liver and intestine) resulting in the formation of methylselenol. (refs 6,7 or (13))

Furthermore, selenomethionine does not produce methylselenol as efficiently as MSC as selenomethionine as many steps are required to produce methylselenol (see metabolism pathway, Figure 1). MSC is also considered to be a better chemopreventive agent as it does not become incorporated into proteins during protein synthesis, whereas selenomethionine can take the place of methionine non-specifically in proteins, and is therefore no available for further metabolism. (13)

There is evidence to support the hypothesis that the “anticarcinogenic effect of selenium is unlikely to be related to its role in maintaining selenoenzymes, especially in situation of adequate selenium nutrition.” (13) Instead, it is believed selenium works as a chemopreventative agent using its ability to “block clonal expansion of transformed lesions” (i.e. the ability to “decrease cell proliferation of the transformed clones”) (13). While testing the effect of MSC on early stage mammary carcinogenesis, it was found that MSC blocked the clonal expansion of premalignant lesions and increased apoptosis (cell death) by nearly a 3-fold increase. (13)

Having theorised that the production of CH3SeH (from MSC via β-lysase - see Figure 1) is vital to the chemopreventive effect, further investigation into CH3SeH was required. However, for in-vitro studies, MSC was found not to be appropriate due to the high concentrations required (which would produce non-specific effects). Therefore, a new selenium compound was used; methylseleninic acid (MSA), CH3SeO2H) (Figure 2). MSA is only required in µM concentrations and easily generates CH3SeH endogenously. Furthermore, a study investigating how MSA inhibited the growth of human premalignant breast cells revealed a 5-fold increase in the level of apoptosis after 24 hours. (13)

Supra-nutritional levels of selenium have consistently been associated with the chemopreventive actions observed, such as around 10 times the level of selenium required to prevent deficiency and allow the correct function of selenoenzymes. (13) (15) However, it is considered unlikely that having such a high level of selenium will have a large impact on the function on selenoproteins. Therefore, it is though that selenium has two different roles in cancer prevention. Firstly, by ensuring that selenium deficiency does not occur allowing the selenoenzymes to function correctly, and secondly, it has been shown that even humans with adequate levels of selenium have shown benefit from metabolizing higher levels of selenium. (reference)

While there is still some uncertainty about the mechanism by which selenium acts against cancer, it is clear that there is a relationship. The results of various clinical trials and research suggest that selenium plays two roles in cancer prevention, firstly as part of antioxidant enzymes and as part of anticarcinogenic metabolites. Based on this information, a model for the role of selenium was produced (Figure 3), which shows that there are several modes by which selenium works as a an anticarcinogen depending on the dose of selenium which is mediated by different functions of selenium.

3.6. Summary

And it is therefore important to continuously produce the active monomethylated metabolite/Many clinical trials have taken place (see section 3.3), in which many forms of selenium were used..... To investigate how this occurs, several studies have been carried out and which are summarised below. Many of the studies were based on evidence that suggests that “selenium acts at an early stage in carcinogensis”. (13)

All of the chemicals found in the metabolism pathway of selenium have been studied. When investigating the metabolism of MSC in rodents (ref 12 from IPC02), it was found that in urine the most abundant metabolite was the monomethylated metabolite, however there were also high levels of the di- and tri-metabolites in breath and urine.

Evidence suggests that selenium can reduce incidence/prevent certain cancers, but doesn't really help to reduce levels/get rid of cancer once you've got it (rephrase)

These studies demonstrated that “selenium supplementation represents a safe and viable way of achieving significant cancer protection”.

4. Platinum based chemotherapy
4.1 Chemotherapy

Chemotherapy works by killing cancer cells using chemicals that interfere with cell division, and result in cell apoptosis. However, one of the main problems with chemotherapy is the damage caused to non-cancerous cells (e.g. cells that rapidly divide such as immune cells, bone marrow and hair follicle cells) during treatment which can result in a range of side effects from nausea to hair loss. (16)

The first chemotherapy drugs were originally based on mustard gas after it was noticed that soldiers exposed died as their bone marrow was destroyed. ‘Nitrogen mustard', an alkylating agent, was first used in 1942 to treat lymphoma patients, with limited success. Since then the understanding of how chemotherapy drugs work has increased resulting in the discovery of many, highly effective chemotherapy drugs. (16)

4.2 Platinum-based chemotherapy

The concept of using platinum-based complexes in chemotherapy was first uncovered, by accident, by Barnett Rosenberg at Michigan State University in the late 1960s. While investigating the effect of applying a magnetic or electric field on cell division, the use of platinum electrodes (believed to be inert), resulted in some electrolysis products which caused the bacteria to appear as long filaments 300 times longer than the normal short rods. These products were identified to contain two active complexes; the neutral cis-isomer [Pt(II)(NH3)2Cl2] (Cisplatin) and a platinum(IV) analogue, cis-diamminetetrachloroplatinum(IV). (17) In 1968 cisplatin (cis-diamminedichloroplatinum(II)) was documented to cause tumour regression, and went on to be used to treat patients from 1971, however, it was not approved by the US Food and Drug Administration (FDA) until 1978. (ref)

The discovery of cisplatin led to an increase in research in platinum-based chemotherapy, which resulted in thousands of cisplatin analogues being synthesized. The aim was to create a drug which would be safer for the patients, and in particular, to decrease the severity of the nephrotoxicity (toxicity/damage to the kidneys) caused by cisplatin. As a result, over time several platinum-based drugs were developed (Figure 4). Carboplatin, which has a “similar spectrum of activity” to cisplatin, was introduced in the 1980's as a second generation analogue with slightly less harsh side effects. Following this came several other drugs including oxaliplatin, satraplatin and picoplatin. (ref) Figure 5 shows the route of development for several of the platinum drugs. (ref)

Many of these drugs are still commonly used today for various forms of cancer. For example, Cisplatin is used for the treatment of testicular and ovarian cancers, while oxaliplatin is commonly used for colo-rectal cancer. However, even though the drugs still work, there is a constant need for the development and improvement of chemotherapy drugs as some tumours become resistant (either via acquired resistance or intrinsic resistance) to the drugs, and therefore become less effective. (ref) By understanding the mechanism by which the drugs work, the mechanism for understanding the resistance to drugs can be determined, and thus can attempt to avoid. In an attempt to get around tumour resistance to cisplatin, new platinum-based drugs, such as oxaliplatin (“active in patients with colorectal cancer”), satraplatin (prostate cancer) and picoplatin were developed. (17) (move to summary?)

4.3 Summary

Is this needed?

5. Selenium as an adjunct in chemotherapy

Having established that selenium does have some chemopreventive properties, and having observed that many cancer patients take vitamin and mineral supplements during treatment, it was advisable to investigate whether taking supplements, such as selenium, while being treated for cancer would either help or hinder the chemotherapy. (delete?) At present, the characterisation of the interaction between antioxidants (such as selenium) and chemotherapy drugs is still poor. There has been some research carried out which is detailed below, however there is evidence to both support and contradict the concept of antioxidants aiding chemotherapy drugs.

5.1 Interactions between selenium and platinum-based drugs

It has been thought that taking selenium supplements can help to reduce certain toxicities related with platinum-based chemotherapy. Cisplatin has been the most extensively investigated platinum-based drug. Platinum-based cancer drugs are known to induce certain toxicities, for example, Cisplatin has been found to cause toxicity predominantly by the formation of free radicals (give examples) which can cause oxidative damage. Antioxidants, such as vitamin E, vitamin C and selenium, are usually used to combat this damage; however it has been found that concentrations of antioxidants within the plasma drop significantly during cisplatin chemotherapy. (2) (18) (19)

It was hoped that by administering selenium during chemotherapy the toxicity of cisplatin would fall. Olas et al. (20) provided evidence to support this as they showed a reduction in toxicity (using sodium selenite) and that the selenium supplementation did not reduce inhibit the antitumour activity of the cisplatin. This was confirmed by a study by Weijl et al. (19) in 2004 where it was shown that when high plasma levels of selenium, vitamin E and vitamin C were recorded, a decrease in “cisplatin-induced ototoxicity and nephrotoxicity” was observed. (19) However, not all patients had high levels of selenium in their plasma. It was unclear if this was due to poor compliance or from inadequate supplementation and called for further investigation. In the same year, Sieja et al. (21) concluded that by administering selenium for 3 months to ovarian cancer patients during chemotherapy resulted in a “significant increase in white blood cells, a significant decrease in hair loss, adnominal pain, weakness, malaise and loss of appetite”. (2) (21)

Furthermore, a study carried out in 1997 investigated a group of 41 patients being treated with cisplatin; a group of 20 patients were given selenium during their first cycle of chemotherapy, but not during the second cycle (to act as a control), while the second group (21 patients) were given the selenium dose in their second cycle, but not in their first. The patients were given 4000µg per day (in the form Seleno-Kappacarrageenan) from the fourth day of their cycle to four days after the cycle. The cisplatin was administered via an IV between the ranges of 60-80mg/m2 on the first day of each cycle. The nephrotoxicity of cisplatin was determined by measuring enzymes in urine samples. When compared to samples taken prior to treatment, the samples after treatment were significantly lower. (22) From this study it was also observed that white blood cell counts were higher, while the volume of blood transfusions and consumption of GCSF were reduced (due to leukopenia) during selenium supplementation. This trial concluded that selenium could be used to reduce nephrotoxicity and leukopenia induced by cisplatin, however the optimal dosage for selenium required further investigation. (22)

Compare different studies above!

5.2 Mechanism for reduction in toxicity

The toxicity of some chemotherapy drugs have been linked to specific oxidative metabolites of valproic acid, VPA, due to the formation of hydrogen peroxide and hydroxyl free radicals. (2) In a study carried out on children, it was noted that patients suffering to a greater extent due to/from? VPA, had elevated levels or glutathione reductase and reduced levels of GSHPx, and concluded that antioxidant activity from selenium played an important role in reducing these effects. (23)

While various drugs have been found to reduce plasma selenium levels, including glucocorticoid drugs and oral contraceptives, this can be counteracted by taking selenium supplements when required. (2)(delete)

5.3 Summary

Combinations - trials not just with selenium. Further research is required

Comment on plasma levels - unreliable?

6. Conclusion

Since the discovery of Selenium in 1817 it has been found to be useful in many areas, from use in the manufacture of glass and ceramics to photoelectric cells and medicine. In particular this review has focused on the role of selenium in cancer prevention. It has been observed that at high levels (often supranutrional) selenium can provide some protection against cancer by acting as an antioxidant.

The form of selenium required for the chemopreventive action is still uncertain, however, a metabolism pathway for selenium within the human body has been constructed and the various selenium compounds studied. (Which forms are most effective)

Platinum-based chemotherapy drugs account for a large proportion of the cancer drugs currently used worldwide, and therefore studying the interaction between selenium and these drugs is highly important. Although there has been some research into the chemopreventive action of selenium, there has only been a limited research into the use of selenium as an adjunct in chemotherapy. Evidence suggests that selenium supplementation can aid in reducing the toxicity of cisplatin without inhibiting the anti-tumour activity of the drug. However, these studies often use a combination of antioxidants, leading to uncertainties surround the precise contribution of selenium, suggesting that further research is required.

The use of new analytical techniques in recent years, such as ICP-MS and gene expression, allow new ways of studying the effect of selenium in cancer prevention by taking direct measurements and studying the pharmacokinetic pathway of various selenium compounds. This is the basis on an ongoing research project being undertaken by the author of this review.

References

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