|Year : 2003 | Volume
| Issue : 1 | Page : 7-13
Prevention of urological cancer
Department of Urology, All India Institute of Medical Sciences, New Delhi, India
M S Ansari
Department of Urology, All India Institute of Medical Sciences, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objectives: Many urological cancers like prostate and bladder have protracted course and maybe ideal for chemoprevention strategies. This article reviews the biology, epidemiology and possible preventive strategies for the various urological cancers.
Methods: The author reviewed the relevant articles published in the last 20 years and studied the biology of the various urological cancers. An attempt is made to identify the various dietary, nutritional and occupationrelated factors implicated in the onset and progression of various urological cancers. The various interventions and clinical trial results are described to prove the relevance of these factors.
Results: Epidemiological reports provide the strongest evidence of protective role for dietary agents in cancer of prostate, bladder and kidney. Cancers of prostate and bladder are uniquely suitable for chemopreventive strategies. For prostate cancer strong evidence exists for a preventive effect of reduced fat intake, vitamin E, selenium, lycopene and soya proteins. Vitamin A administration shows a strong inverse relation to bladder cancer. Better prevention is seen with combination of high doses of vitamins A, C, E and B6. High-energy intake is related to the higher incidence of renal cell carcinoma (RCC). While vitamins D and E supplementation has resulted in lower incidence of RCC.
Conclusions: Numerous studies implicate dietary and nutritional factors in the onset and progression of various urological cancers. Hence, it is possible that bioactive compounds (anti-oxidants) like vits. A, D, C, and E, minerals like selenium and carotenoids like lycopene along with reduction of animal fat in diet can be a part of preventive strategies for various urological cancers.
Keywords: Prevention, urological cancer.
|How to cite this article:|
Ansari M S. Prevention of urological cancer. Indian J Urol 2003;20:7-13
| Introduction|| |
Cancer is a multifactorial, multifaceted and multimechanistic disease requiring multidimensional approach for its treatment, control and prevention. Carcinogenesis involves fundamental biological process concerning initiation and promotion in the form disorganized cell replication, cell death, and disorganization of organ structure. Cancer prevention and chemoprevention are considered as a strategy to block or reverse carcinogenesis from the very early stages. The goals can be achieved through dietary changes, prevention of occupational exposure or administration of chemopreventive agents, which, may be a part of a modified diet or a synthetic pill with vitamins and minerals. ,
| Methods|| |
The author reviewed the relevant articles published in the last twenty years and studied the biology of the various urological cancers. An attempt is made to identify the various dietary, nutritional and occupation-related factors implicated in the onset and progression of various urological cancers. The various interventions and clinical trial results are described to prove the relevance of these factors.
| Definition of Cancer Prevention and Chemoprevention|| |
A resurgence of interest in cancer prevention and control has occurred in United States since the passage of the National Cancer Act in 1971 by the National Cancer Institute (NCI). Cancer prevention and control was defined as "the reduction of cancer incidence, morbidity and mortality through an orderly sequence, from research on interventions and their impact in defined populations to the broad, systematic application of the research results. This effect of cancer prevention should ideally run through a national programme, an explanation of the principal elements of the definition are described through [Figure - 1]. A methodological and comprehensive approach is given below, which can be easily applied on community basis [Figure - 2].
Chemoprevention refers to the prevention or prolongation of the onset of carcinogenesis by intervention with the agents to prevent, suppress, or reverse malignant transformation. The various bioactive compounds, which act as anti-oxidants and scavengers combine to the target tissues and protect the body against the harmful effects of free radicals which would otherwise combine to these tissues through mitochondrial oxidase system [Figure - 3]. Free radical is an atom or molecule that has one or more unpaired electrons; its consequent tendency to acquire an electron makes it highly reactive. Antioxidant is defined as any compound, which breaks the free radical reaction chain. Ideal chemopreventive agent should be nontoxic, efficacious, easily available and inexpensive. Chemopreventive agent can be provided as a part of modified diet or synthetic derivatives. Chemopreventive agents (CPA) are classified as: i) Inhibitors of initiation, ii) Anti-promotional agents, and iii) Inhibitors of progression.
| Carcinoma of the Prostate|| |
Prostatic carcinoma, in the male population ranks first as incidence and second as cause of oncological mortality. Carcinoma of the prostate is considered to be ideal for chemoprevention because of the following reasons: i) It has got a protracted course (long latency time), ii) A high incidence rate, iii) Availability of an effective marker like serum PSA and, iv) Hormone dependency. Currently there are many epidemiological and experimental studies undergoing to scrutinise the role of various biological agents in chemoprevention of prostate cancer.
A study by the American Cancer Society has shown that obesity increased the risk of prostatic cancer . 
Epidemiological studies: Prostate cancer is one of the most common male cancers in Western countries, yet the incidence of this fatal disease remains low in Asian populations. A high phytoestrogen intake through vegetarian diet may be one factor contributing to the low prostate cancer mortality in Eastern populations. While the high fat intake in western diet is now well related with higher incidence of prostate cancer. , A key component of the recommended diet is illustrated by the Food Guide Pyramid issued by US department of Human Nutrition and Information service.
It is a fat-soluble vitamin, which occurs in nature as retinol and dehydroretinol. Synthetically it is derived from carotenoids (betacarotene).
Animal studies: Carotenoids (retinol and retinoic acid) interact with specific intracellular receptors and affect protein synthesis, finally controlling cell chromatin, cell growth and cell differentiation. Fenretinide (N-4-hydroxyphenyl retinamide), a vitamin A analogue has shown a lowered incidence of tumor by 49% and tumour mass by 52% as compared to normally fed animals and in LN CaP cell line culture. 
Human studies: Vitamin A and its analogues modulate the growth and differentiation of cancer cells presumably by activating gene transcription via the nuclear retinoic acid receptor (RAR). 
Calcitriol (1,25-D3) is the active form of Vitamin D, which is produced in the skin by ultraviolet radiation of 7dehydrocholesterol.
Epidemiological studies: A lower level of 1,25-D3 is associated with increased incidence of carcinoma of the prostate and an inverse relationship was observed between skin exposure and mortality rate for carcinoma prostate. 
Animal studies: Vitamin D3 inhibits cell proliferation, promotes cell differentiation and selectively decreases level of type IV collagen in carcinoma of the prostate tumor cells. 
Human studies: Human trials have shown that receptors for vitamin D (lalpha, 25-dihydroxyvitamin D3) exist in human carcinoma of the prostate (CaP) cell lines like, LN CaP, PC-3 and DU 145. ,
It occurs in the nature as a mixture of several closely related compounds called as tocopherols. It is an important natural antioxidant and scavenger. Due to its lypophilic character, it accumulates in circulating lipoproteins, cellular membranes and fat deposits, where it reacts very rapidly with molecular oxygen and free radicals.
Epidemiological studies: Eichholzer et al (1996) in their study observed that men with low plasma levels of vitamin E had an increased risk of carcinoma of the prostate. 
Animal studies: Dietary vitamin E produces 30-60% inhibition of induced carcinogenesis due to its ability to inhibit synthesis of nitrosamine compounds. 
Human studies: Human, alpha-Tocopherol Beta-Carotene Cancer Prevention Study (1995) showed that man receiving Vit. E had a 34% lower incidence of carcinoma of the prostate. 
Vitamin C is a six-carbon organic acid with structural similarity to glucose. It is a potent reducing agent in several hydroxylation reactions making it capable of reducing (scavenger) compounds like molecular oxygen and nitrates. It inhibits malignant transformation, decreases chromosomal damage in the cell.
Epidemiological studies : A decreased risk of lower urinary tract cancer has been shown with increased vitamin C intake in a study of patients matched for age, sex and ethnic groups to two population based controls. 
Animal studies: When treated with vitamin C, tumor cell lines showed reduced viability for both DU 145 (androgen independent) and LN CaP (androgen dependent). Vitamin C induces these changes by interfering at the level of production of hydrogen peroxide, which in turn produces free radicals that damage the cells. 
It is an important component of metalloenzyme glutathione peroxidase, which destroys peroxides in cytosol. It acts as a synergistic anti-oxidant with Vitamin E.
Human studies: The risk of prostate cancer for patients with low serum selenium levels reported up to twice that of subjects with high levels. Supplementation of selenium in diet has resulted in lower incidence of prostate cancer. ,
Lycopene is a carotenoid, which is found in high levels in some fruits and vegetables. Lycopene acts as an antioxidant and prevents damage to DNA by singlet oxygen damage.
Human studies: Prospective randomised controlled trials have shown a lower prostate cancer risk in men with elevated plasma lycopene levels. The antiproliferative and inhibitory effect of lycopene on prostate cancer cells has been well documented in controlled trials. 
Nonsteroidal anti-inflammatory drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) play a potential role in chemoprevention by inhibiting prostaglandin synthesis. Western and northern blot analyses demonstrated that flufenamic acid (FA) inhibited the androgen receptor (AR) expression at mRNA and protein levels when used on LN CaP cells, an androgen-responsive human prostate carcinoma cell line. 
Ornithine decarboxylase (ODC), a rate-controlling enzyme in the polyamine biosynthetic pathway, is over expressed in carcinoma of the prostate and prostatic fluid in humans. Green tea polyphenols (GTPs) are capable of modulating ODC hence, possesses strong chemopreventive properties against a variety of animal tumor models. 
| Carcinoma of the Bladder|| |
Natural history and carcinogenesis
Carcinoma of the bladder accounts for 10% and 4% of all malignancies for men and women respectively making it the fourth leading cause of death. Most bladder tumours (70%) are classified as superficial, which is the target for cancer prevention. Bladder cancer is most prominent among human neoplasms in having been associated pathogenetically with many etiological factors. Transitional cell carcinoma like adenocarcinoma of prostate has a protracted course and may be just right for chemoprevention.
Prevention of occupational exposures for cancer risk
One of the most successful forms of prevention is to detect carcinogenecity of a substance in advance, and as a result never to introduce it into the work place. The high risk of bladder tumours in men engaged in work with various aromatic amines in the dye industry was shown in the classic studies by Case and colleagues over 45 years ago in 1954. Similarly, high incidence of carcinoma of the bladder was shown amongst rubber factory workers employed in British rubber industry.
Many laboratory studies and human epidemiological data suggest that most cancer deaths are attributable to lifestyle, including nutritional factors and tobacco and alcohol consumption. The risk of bladder cancer in smokers is nearly 2-4 times as compared to general population. Tobacco use in combination with exposure to other carcinogens further increases the risk of bladder cancer. 
Dietary fat, soyabean foods and garlic (Allium sativum)
Many epidemiological studies have shown a direct relationship between dietary fat and the risk of bladder cancer. Hence, a low calorie and low fat (specially low cholesterol) diet is protective. Isoflavones are excreted in human urine and can be modulated by soya-rich diets. Recently, isoflavones (genistein, daidzein and biochanin) were suggested to have protective effects against bladder cancer cells justifying the potential use of soyabean foods as a practical chemoprevention approach for patients with urinary tract cancer. Garlic acts as an antioxidant that interact with P-450 enzymes inhibiting the conversion of procarcinogen to carcinogen, immunomodulator and a direct inhibitor of cancer cells hence, garlic has a preventive role in bladder cancer. ,
Animal studies: Wolbach and Hove, undertook the first animal study and it was found that diet deficient in vitamin A caused squamous metaplasia of rat urothelium, which was fully reversible by restoring a normal diet containing vitamin A.
Human studies: In humans, two randomised studies used the orally active synthetic retinoid etretinate daily against a placebo group after resection of all visible bladder tumour. It was seen that mean interval of recurrence was longer as well as the number of subsequent transurethral resections were less in etretinate group.
Animal studies: In vitro, VitC:VitK3-treated cells showed exaggerated membrane damage and an enucleation process in cancer cells. Vitamin induces cell death in cancer cells and prevents the normal cell damage by free radicals. 
Human studies: L-ascorbic acid has been shown to reduce the elevated level of urinary chemiluminescence found in patients with bladder cancer. 
Vitamin B6 (Pyridoxine)
Vitamin B6 is a co-enzyme involved in the biosynthesis of thymidine. Thymidine deficiency has been reported to increase DNA replication errors and hence increase mutagenesis.
Animal studies: It has been proposed that the naturally occurring vitamin B6 compound, pyridoxine, enhances TNF-induced cytolysis of three subclones of a mouse fibrosarcoma cell line (WEHI 164) and tumour inhibition mediated by T lymphocyte-dependent mechanisms. 
Human studies: Tryptophan metabolites are known to cause bladder cancer. Pyridoxine administration reverses the abnormalities of tryptophan metabolism thus preventing the recurrences of superficial bladder cancers. 
Experimental studies: It inhibits N-nitroso compounds synthesis during carcinogenesis and reduces DNA synthesis, hence inducing apoptosis.
In vitro experiments with L 1210 cells exhibited a moderate protection by the addition of this scavenger of free radicals. 
Experimental studies: Calcitriol inhibits proliferation and induces apoptosis in human bladder tumor cells in vitro. The 253j and T-24 cell lines proliferation was significantly inhibited by calcitriol. 
Human studies: The presence of vitamin D receptors in normal and neoplastic human bladder tissue, and tumor cells T-24 and 253j has been determined by immunohistochemical and immunoblot analysis. Through these receptors vit. D inhibits cancer cell proliferation. 
Epidemiological studies: Epidemiological studies have shown significantly low levels of selenium in blood samples of patients who developed bladder cancer.
Animal studies: A prospective study revealed the inhibitory effect of sodium selenite on induction of bladder cancer by butylbutanolnitrosamine in rats. The incidence of carcinoma in the control group was 87.5% whereas in the sodium selenite group as 50%. 
Difluoromethylornithine (DFMO), Nonsteroidal anti-inflammatory drugs (NSAIDs) and Cox-2 inhibitors
DFMO a potent irreversible inhibitor of the enzyme ornithine decarboxylase (ODC), that catalyses the synthesis of putriscine, a polyamine involved in the synthesis of DNA.  Prostaglandins (PGs) produced by cyclooxygenases (COXs) are represented by a large series of compounds that mainly enhance bladder cancer development and progression. Selective inhibitors of COX-2 and LOX are now described, including nonsteroidal anti-inflammatory drugs to take a place in bladder cancer prevention. ,
| Renal Cell Carcinoma (RCC)|| |
Renal cell carcinoma, although occurring less frequently than prostate and bladder cancers, is actually the most malignant urologic disease, killing more than 35% of affected patients. There are no data on the epidemiology of premalignant lesions of the kidney, but research into the etiology of RCC has been extended substantially. Cigarette smoking and obesity are established risk factors for RCC. The various vitamins and dietary measures, which have been under scrutiny as chemopreventive measures, are as follows.
Several energy sources have been identified as possible risk factors for renal cell carcinoma. It is possible that a high-energy intake with dairy fats may be associated with renal cell carcinoma risk. In a population-based case-control study in Denmark, including a total of 351 cases, a positive association was observed between risk of renal cell carcinoma and total energy and fat intake.
Epidemiological studies: It has been seen that the serum level of beta-carotene and retinoic acid are low in patients with RCC. 
Human studies: Diet rich in orange and dark green vegetables has been protective against RCC. 
Epidemiological studies: Diet poor in vitamin E has been found with increased risk of RCC and diet rich in vitamin E has been protective especially in non-smokers. 
Human studies: In a study, blood levels of vitamin E and total lipids in patients with renal cell carcinoma were significantly higher than in healthy subjects.  There are anecdotal reports of spontaneous resolution of metastasis with vitamin E therapy supporting its protective role in RCC. 
Epidemiological studies: A population-based case-control study was conducted in non-Asians of Los Angeles, which included 1,204 patients of RCC. The study revealed strong inverse association between cruciferous and dark green vegetable intakes and RCC risk. 
Epidemiological studies: It has been found that a decrease in the serum vit. D level is one of the risk factors for development and progression of RCC.
Experimental studies: Vit. D3 may prevent RCC by preserving gap junctional intercellular communication (GJIC) during carcinogenesis. In a study, BALB/c mice were inoculated with murine renal cancer cells. Vit. D3 inhibited tumor growth and prolonged the life span of Renca-bearing mice in a dose-dependent manner. 
| Conclusions|| |
Numerous studies implicate dietary and nutritional factors in the onset and progression of various urological cancers. Hence, it is possible that bioactive compounds (anti-oxidants) like vits. A, D, C and E minerals like selenium and carotenoids like lycopene can be a part of chemopreventive strategies for cancers of prostate, bladder and kidney. Reduction of animal fat in diet and increased consumption of fresh fruits and vegetables show a strong and inverse association with these malignancies. Ongoing studies on nutrition and carcinoma prostate (CaP), bladder (CaB) and renal cell carcinoma (RCC) may bring the required evidence to support what is still only a hypothesis at present. However, absolute recommendation will have to await the results of long-term prospective clinical trials. Successful completion of such a study could lead to a changed view of how the patients with urologic malignancy are managed and provide insight into the management of such dreaded diseases. The goals of any study can be met in a better way through a national programme, when it needs to be implemented on a large scale or countrywide basis. A country like United States is running a national programme for cancer prevention and control under National Cancer Act (1971). India also needs to formulate a national plan and a methodological strategy to carry out broad intervention research to reduce not only the incidence of various urologic malignancies but also to reduce the mortality rate.
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[Figure - 1], [Figure - 2], [Figure - 3]