Elsevier

The Lancet Oncology

Volume 7, Issue 9, September 2006, Pages 766-774
The Lancet Oncology

Review
Use of selenium in chemoprevention of bladder cancer

https://doi.org/10.1016/S1470-2045(06)70862-2Get rights and content

Summary

The anticarcinogenic potential of selenium was first identified nearly 40 years ago in geographical studies that reported lower death rates for cancer in regions with high levels of selenium. Cancer of the bladder was one of the body sites found to share this inverse association. Although many subsequent studies have been done on selenium and cancer, only a few have specifically assessed the relation with bladder cancer. However, the high recurrence rate and ability to monitor bladder urothelial-cell carcinoma make selenium a good candidate for chemoprevention. Evidence suggests that selenium is a biologically plausible, safe, and efficacious potential chemoprevention agent for bladder cancer. Large tertiary chemoprevention trials are needed to further investigate the role of selenium in the prevention of bladder cancer. Future studies should assess the best dose and form of selenium, and whether the protective effect of selenium differs between the sexes.

Introduction

Bladder cancer is a major health problem and ranks the ninth most common cancer for both sexes worldwide.1 In 2002, 357 000 new cases and 145 000 deaths were attributed to the disease.1 About 90% of bladder cancer cases are transitional or urothelial-cell carcinomas, with the remainder comprising adenocarcinomas, small-cell carcinomas, and squamous-cell carcinomas.1 Cancer of the bladder affects mainly elderly people, with a median age at diagnosis of 65–70 years.2 This cancer is more common in men (77% of bladder cancer cases) and 63% of cases are from high-income countries.1 Clinically, two types of bladder cancer are evident: papillary and invasive. Papillary bladder cancer is derived from superficial tumours (stage Ta–T1) and confined to the urothelium (figure 1).3 Although rarely lethal, papillary bladder cancer recurs in up to 75% of patients.3 Only a few of these patients progress to invasive bladder cancer, which develops through carcinoma in situ.3 This type of bladder cancer has the potential to be highly malignant and progressive, and can metastasise and lead to death (figure 2).3

Most cases of bladder cancer are sporadic, and involve no known family history.4 Long-term exposure of the urothelium to carcinogens is thought to cause bladder cancer.4 Cigarette smoking is reported to be the major risk factor for the disease.5 Other factors have also been implicated in its cause, such as radiation, schistosomal infections, and exposure to chemicals (eg, aromatic amines and polycyclic aromatic hydrocarbons).6 Polymorphisms of genes involved in the metabolism of carcinogens—glutathione S transferase (GST), N-acetyltransferase (NAT), and sulphotransferase (SULT)—are thought to modify an individual's susceptibility to carcinogens and hence their potential risk to cancer.7 From a dietary perspective, high consumption of meat and fat, and high total fluid intake have also been associated with bladder cancer.8 However, results from studies investigating these dietary factors have been inconsistent and inconclusive.8 From existing information on the nutritional factors that are thought to reduce the risk of bladder cancer, several studies8, 9, 10 have reported that a diet high in fruit, vegetables, vitamins A, C, and E, and the trace element selenium might be protective.

Because geographical studies11, 12 done in the 1970s reported a possible inverse association between selenium and cancer mortality, epidemiological studies have focused on investigating the anticarcinogenic properties of this nutrient. Two key findings that emerged from these early studies were the inverse association between selenium and cancer seemed to be both sex and site specific. A larger difference in the reduced death rates was reported for men than for women in regions with high levels of selenium, and mortality was significantly lower for some types of cancer (eg, bladder cancer).11, 13 We reviewed the available published work to determine whether selenium is a suitable chemoprevention agent for bladder cancer.

Section snippets

Sources of selenium

Selenium is an essential trace element that is present in a wide range of foods, including grains, meat, poultry, fish, eggs, and dairy products.14 Large variations in selenium intake exist between populations. The soil content of an area generally determines the amount of selenium available in the food supply.15 Regional differences in the soil content of selenium range from 0·1 μg/kg to 1000 mg/kg.16 Areas of China (eg, Sichuan Province), New Zealand, Finland, and the Balkans are reported to

Selenium metabolism

Selenium can be classified into two basic chemical forms: organic selenium (selenomethionine and selenocysteine) and inorganic selenium (sodium selenite and selenate). Organic and inorganic selenium are thought to have different bioavailability, anticancer mechanisms of action, and toxic effects.19 Selenium in both its forms and in its reduced states is distributed widely throughout the body. The metabolism of selenium is thought to be involved in many biochemical pathways (figure 3). Hydrogen

Selenium biomarkers

Exposure to selenium can be determined through dietary intake or the presence of biomarkers.17 Both methods have advantages and disadvantages. Difficulties associated with using only dietary assessment include the wide variation in the selenium concentration in the food supplies in different populations, food import and export between countries, and recall bias leading to underestimation or overestimation of intake.21 Alternatively, selection of the most appropriate biological sample to

Selenium and bladder cancer

Although the actual anticarcinogenic effects of selenium are not fully understood, several explanations have been proposed. The antioxidant role of selenium has been consistently reported. Oxygen reactive species cause damage to DNA and can lead to carcinogenesis.36 Selenium-dependent glutathione peroxidase is a selenoenzyme that protects against oxidative stress to the DNA and cell membrane by removing hydrogen peroxides and lipid hydroperoxides from the cells.37 Selenium metabolites such as

In vitro studies

Studies done in vitro have focused only on the effects of selenium on cells from body sites other than the urinary bladder. However, results from these studies have underscored the difference in the doses and mechanism of actions between the two types of selenium. Inorganic selenium compounds in cell cultures can induce single-strand breaks in DNA and necrosis at concentrations of 5–10 μmol/L.38 Alternatively, organic selenium compounds caused apoptosis without DNA breakage at higher

Studies done in animals

More than 100 studies have been done in animals to investigate selenium and cancer. About two-thirds of these studies have reported a decreased incidence in cancer after selenium supplementation, and half of the reductions have involved a decrease of 50% or more.37 One of the few available animal studies45 on selenium and bladder cancer investigated the effect of low glutathione enzymes on the risk of carcinogenesis in the bladder. This comparative study assessed the urinary bladder of rabbits

Epidemiological studies

Only a few epidemiological studies have specifically investigated the association between selenium and bladder cancer. These studies have been heterogeneous in terms of study populations, selenium measures, and study designs (table 1). Prospective designs, such as cohort, nested case-control, and case-cohort studies, in which exposure measures are taken before diagnosis, are preferred for investigating the relation between exposure and disease.21

A large prospective study9 that included 431

Clinical trials

Only a few clinical trials have been done to investigate selenium supplementation to reduce cancer incidence in humans. Results from the Nutritional Prevention of Cancer (NPC) trial,65 which investigated the relation between selenium and non-melanoma skin cancer, generated many investigations into selenium as a potential chemoprevention agent. The NPC trial gave 1312 patients either 200 μg selenised yeast or placebo every day for a mean of 4·5 years (SD 2·8) with a mean follow-up of 6·4 years

Chemoprevention

Until the SELENIB trial, no chemoprevention trials have been done on bladder cancer. Chemoprevention comprises three types: primary, secondary, and tertiary. Primary chemoprevention refers to the use of agents to prevent the initiation of carcinogenesis.66 Because of the long latency period of bladder cancer, very large studies are needed to evaluate a primary chemoprevention strategy.66 Secondary chemoprevention uses the agent to prevent premalignant lesions from developing into malignant

Conclusions

Despite early reports suggesting that selenium concentrations were inversely associated with risk of bladder cancer, only a few studies have assessed this specific relation. Although the exact anticancer mechanism of action of selenium is not fully known, selenium in its various forms might have the potential to act in both the early and late stages of the carcinogenic pathway.21 Further studies in animals and in vitro should help us to understand the role of selenium in the initiation,

Search strategy and selection criteria

Material included in this review was identified from computerised searches of PubMed (1966 to March, 2006), EMBASE (1974 to March, 2006) and Current Contents (1998 to March, 2006) using the medical subject headings (MeSH) terms “bladder neoplasms OR carcinoma”, “transitional cell AND selenium”. Free text terms “selen* AND bladder cancer AND chemoprevention” were also used and combined with “clinical trials”, “epidemiologic studies”, “animal studies”, and “in-vitro studies”. Only

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