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Chemoprevention of carcinoma prostate. a review

International Urology and Nephrology 34: 207–214, 2002.
2003 Kluwer Academic Publishers. Printed in the Netherlands. Chemoprevention of carcinoma prostate: A review
M.S. Ansari, N.P. Gupta & A.K. HemalDepartment of Urology, All India Institute of Medical Sciences, New Delhi-110029, India Abstract. Purpose: Chemoprevention of prostate cancer is the administration of agents to prevent, inhibit,
or delay progression of prostate cancer. Opportunities exist for testing various types of chemopreventive
interventsion. Material and methods: The authors reviewed the relevant articles published in the last twenty years
and studied the biology of the prostate cancer. An attempt is made to identify intermediate markers and surrogate
endpoint markers. The various interventions and initial clinical trial results are described. End points for evaluation
are mainly based on changes in PSA, changes of histological precursors, or time of onset of clinical disease.
Results: Nutritional factors such as reduced fat intake, vitamin A, vitamin E, vitamin C, vitamin D, Lycopene
and selenium may have a protective effect against prostate cancer. Conclusion: Numerous studies implicate
dietary and nutritional factors in the onset and progression of prostate cancer. Hence, it is possible that bioactive
compounds (anti-oxidants) like vits. A, C, D, E, minerals like selenium and carotenoids like lycopene can be a
part of chemopreventive strategies for prostate cancer. Ongoing studies on nutrition and prostate cancer 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.
Introduction
chemopreventive agents. In addition to their estro-genic activity, many of these plant compounds can Prostatic carcinoma, in the male population ranks interfere with steroid metabolism and bioavailability first as incidence and second as cause of oncologic and can also inhibit enzymes, such as tyrosine kinase mortality. The present trends of the clinical research or topoisomerase, which are important for cellular in this field are directed towards the identification of proliferation [41]. A great number of publications factors involved in the onset of this neoplasm and the have dealt with a number of nutritional factors such as possibility of decreasing its incidence with programs reduced fat intake, phytoestrogens, vitamin E, vitamin of chemoprevention, the identification of new biolo- D, and selenium and inferred that these may have gical markers able to assess the biological potential a protective effect against prostate cancer. The fact of the disease. An overview of the prevention of was proven in large epidemiological studies as well this important condition is given in this article, and as experimental observation. In the animal model, the diagnostic markers along with possible experimental progression of established tumors can be inhibited by models for prevention or prolongation of carcinogen- esis are presented in brief. The large variability inthe incidence of the tumor in different geographicalregions suggests the possibility of nutritional influ- Discussion
ences regarding the stimulation and/or inhibition ofclinical cancer, as there is a similar prevalence world- Over the last decade, the Chemoprevention Branch, wide of the precursor lesion. Epidemiological studies Division of Cancer Prevention and Control, National have shown that the Asian men have a much lower Cancer Institute, USA; has been developing drugs that incidence of prostate cancer than men in Euorpe or will slow or stop the progression to invasive cancer of the USA. Asian food includes low-fat, high-fiber precancerous (pre-invasive) lesions generally termed diets, which provide a rich supply of weak dietary ‘intraepithelial dysplasia’ or ‘dysplasia’. Over 40 estrogens. These entrogens have been proposed as short-term clinical trials are in progress [5]. Cancer prevention refers to the prevention or prolongation neoplasia (PIN) and atypical adenomatous hyperplasia of the onset of carcinogenesis by intervention with (AAH). Clinical studies suggest that PIN predates the agents to prevent, suppress, or reverse malignant carcinoma by 10 years or more, with low grade PIN transformation [3]. Why carcinoma prostate has been first appearing in men in their 30s. Unlike PIN, AAH chosen for chemoprevention strategies? Carcinoma is weakly linked to carcinoma. It was stated that this prostate is considered to be ideal for chemoprevention family of cell lines with a common lineage represents a unique and relevant model which mimics stages in i. It has got a protracted course (long latency time).
prostatic intra-epithelial neoplasia (PIN) and progres- sion to invasive cancer, and can be used to study iii. Availability of an effective marker like serum PSA.
carcinogenesis, progression, intervention, and chemo- iv. Possible availability of a genetic marker (P53) that prevention [39]. Lopaczynski et al. (2001), in prepro- can be used as an end point of prostate cancer statectomy model observed that IGF system appears to play an important role in the development of prostate cancer by modulation of paracrine pathways, and The study of prostate carcinogenesis and tumor pro- also by modulation of the concentrations of different gression is made difficult by the lack of appro- stromal and epithelial IGFBP, which are differentially priate in vitro and in vivo models. High preval- expressed in the epithelium and stroma. Nerve growth ence intra-epithelial neoplasia and latent prostatic factor is capable of stimulating a proliferative response carcinoma, representing multiple steps in carcino- via a high affinity Trk receptor present in normal genesis to invasive carcinoma, are relevant targets and malignant prostate epithelia, and alternatively for cancer prevention. Webber et al. (2001) derived can mediate apoptosis via the low affinity p75NTR four tumorigenic cell lines with progressive malig- receptor that is progressively lost from the malig- nant characteristics. The MNU cell lines, in order of nant prostate. As the role of each stromal element increasing malignancy were; WPE1-NA22, WPE1- involved in carcinogenesis becomes further defined, these elements offer promising targets for new chemo- ment of effective chemopreventive agents for human preventive strategies [21]. There is a tremendous need consumption requires conclusive evidence of their for exposure biomarkers, which need to function as efficacy in animal models that have relevance to intermediate end-points in cancer chemoprevention human diseases. Transgenic adenocarcinoma mouse studies. Imbalance between cell proliferation and cell prostate (TRAMP) is an excellent model of prostate apoptosis has been considered a key factor in carci- cancer that mimics progressive forms of human nogenesis. Prostatic intraepithelial neoplasia (PIN) is disease inasmuch as 100% of males develop histolo- the most likely precancereous lesion and represents the gical PIN by 8–12 weeks of age that progress to adeno- major target for chemoprevention of prostate cancer carcinoma. In these animals, ornithine decarboxylase [41]. High-grade prostatic intraepithelial neoplasia (ODC) activity (> 3-fold) as well as protein expres- (HGPIN) has also been investigated as an interme- sion (> 4-fold) was found to be markedly higher diate biomarker for prostate cancer. Endocrine therapy in the dorsolateral prostate as compared with the changes the morphology of PIN, hampering its iden- nontransgenic littermates, suggesting their suitabi- tification by making it more closely resemble the lity to determine the chemopreventive effect of normal benign glands. Androgen deprivation therapy alpha-difluoromethylornithine (DFMO), an enzyme- decreases the prevalence and extent of PIN, suggesting activated irreversible inhibitor of ODC, against that this form of treatment may play a role in chemo- prevention [8, 9]. Cessation of endocrine therapy islikely to lead to renewed expansion of PIN, since PINcontinues to express androgen receptors and the cell- Prostatic intraepithelial neoplasia: A marker for
cycle protein MIB-1 under conditions of low androgen high-risk groups and a potential target for
levels. HGPIN has the advantage that it appears to be chemoprevention
quite highly proximal to the development of cancerand to be modifiable [18, 23]. Loss of expression of The search for the precursor of prostatic adenocar- the pi-class glutathione S-transferase enzyme GSTP1, cinoma has focused in recent years on two histopath- which is associated with the hypermethylation of ologic findings: high grade prostatic intraepithelial dexoycytidine residues in the 5 -regulatory CG island region of the GSTP1 gene, is a near-universal finding of chemopreventive agents. Recommended chemo- in human prostate cancer. Likewise high-grade PIN prevention strategies based on these mechanisms are is completely devoid of GSTP1. Hypermethylation of (i) the development of better technology for early the 5 -regulatory region of the GSTP1 gene may serve diagnosis, (ii) the development of multiple agents as an important molecular genetic biomarker for both that block intralesional proliferation at steps along the signal pathway of mitotic signal transduction andalong the signal pathway of sythnesis of daughter cellcomponents, (iii) the development of nontoxic anti- Animal models in defining efficacy of
inflammatory agents, antioxidants, antimutagens, andproapoptotics, (iv) the avoidance of ‘clonal escape’ chemoprevention agents against prostate cancer
through use of drug combinations, and (v) the use ofcomputer-assisted quantitative image analysis to assay Animal models are crucial in preclinical efficacy modulation of surrogate end points in chemopreven- testing of chemoprevention agents. The most feasible, tion clinical trials [6]. Ideal chemopreventive agent realistic, and potentially effective target for prostate should be nontoxic, efficacious, easily available and cancer chemoprevention is progression from prostatic inexpensive. CPA can be provided as a part of modi- intraepithelial neoplasia (PIN) to histologic cancer and fied diet or synthetic derivatives (Pills). The various from histologic to clinically manifest cancer. There possible chemopreventive agents and measures for are transgenic mouse models for prostate cancer and models for PIN, but these have not yet been fully developed and evaluated for chemoprevention studies.
Human prostate cancer xenografts in mice and trans- plantable Dunning rat prostate carcinomas can be used to assess tumor growth inhibition. PIN occurs mostly • Hormonal manipulation: Flutamide, Dehydroepi- in these two models, and metastases are frequent in some transgenic models and the MNU-testosterone • Miscellaneous compounds: Nonsteroidal anti- rate model [7]. The three most widely used carcinoma cell liens, DU-145, PC-3, and LNCaP, developedbetween 1977 and 1980, have greatly contributed toour present understanding of prostate cancer. These Vitamin A
cell lines will further serve as useful models forinvestigating tumor progression, invasion, metastasis, Fat soluble vitamin, which occurs in nature as new therapeutic strategies, drug resistance and its retinal and dehydroretinol. Synthetically it is derived from carotenoids (betacarotene). Carotenoids retinaland retinoic acid interact with specific intracel-lular receptors and affect protein synthesis finally Chemopreventive strategies
controlling cell chromatin, cell growth and cell differ-entiation [20]. There are over six human retinoid Chemopreventive agents (CPA) are classified as (i) receptors (RAR [α, β and χ ] and PXR [α, β and χ ]) Inhibitors of initiation, (ii) Anti- promotional agents and all six belong to the steroid receptor superfamily.
and (iii) Inhibitors of progression.
Vitamin A and its analogues modulate the growth and bioactive compounds which act as anti-oxidants and differentiation of cancer cells presumably by activa- scavengers combine to the target tissues and protect ting gene transcription via the nuclear retinoic acid the body against the harmful effect of free radicals receptor (RAR) alpha, beta, and gamma and retinoid which would otherwise combine to these tissues X receptor (RXR) alpha, beta, and gamma [35].
(Figure 1). Free radical is an atom or molecule that Fenretinide (N-4-hydroxyphenyl retinamide) (4HPR) has one or more unpaired electrons its consequent a vitamin A analogues has been found to be rela- tendency to acquire an electron makes it highly tively nontoxic in preclinical experiments and early reactive. Antioxidant is defined as any compound, clinical trials. Experimental studies have shown in which breaks the free radical reaction chain. Different Mouse prostate reconstitution model system, Fenre- mechanisms have been proposed for various kinds tidine showed a lowered incidence of tumor by 49% Figure 1. Mitochondrial cytochrome oxidase system.
and tumor mass by 52% as compared to normal fed tion possibly explained by a more rapid degradation.
animals and in LN Cap cell line culture. Fenretidine However, the Alpha-tocopherol Beta-carotene Cancer produced 82–95% suppression of cell growth, partial Prevention study in a placebo controlled, randomized arrest in G1 phase of cell cycle and marked increase in trial showed that betacarotene treatment resulted in the number of apoptic cells [34]. The chemopreventive increase in cancer at the lungs, prostate and stomach.
effect of retinoids is most likely exerted at the tumor- This effect was more evident in alcoholics, which promotion phase of carcinogenesis. Retinoids block might shift the dose response curve. Another possibi- tumour promotion by inhibiting proliferation, indu- lity could be that an excess administration may reduce cing apoptosis, inducing differentiation, or a combi- the efficacy or even promote tumors [3].
nation of these actions [25]. It has been proposedthat in prostate cancer, urokinase-type plasminogenactivator (u-PA) is the key enzyme which occupies Vitamin D
a place at the apex of the proteolytic cascade andinitiates the degradative process needed for ability to Calcitriol (1,25-D3) is the active form of vit. D invade and metastasize. All-trans retinoic acid (RA) which is produced in the skin ultraviolet radia- reduced the ability of u-PA-mediated degradation of tion of 7-dehydrocholestol. Epidemiological studies fibronectin and laminin [37]. Animal studies proved have shown that a lower 1,25-D3 is associated that prostate carcinoma tissue contains 5–8 times less with increased incidence of carcinoma prostate and retinoic acid than normal prostate or BPH. The lower an inverse relationship was observed between skin retinoic acid content may contribute to cancer devel- exposure and mortality rate for carcinoma prostate opment or just be a marker of cellular transforma- [31, 33]. Animal studies have proved that vit. D3 inhibit cell proliferation, promote cell differentiation and lung. A decreased risk of lower urinary tract and selectively decreases level of type IV collagen cancer has been shown with increased vitamin C in carcinoma prostate tumor cells [32]. Human trials intake in a study of patients matched for age, sex and have shown that receptors for vitamin D (1alpha, 25- ethnic groups to two population based controls [26].
dihydroxyvitamin D3) exist in human prostate cancer Animal studies have shown that when treated with cell lines like, LN Cap, PC-3 and DU 145 [33].
vit. C both tumor cell lines showed reduced viabi- The ubiquitous presence of vitamin D receptor and lity for both DU145 (androgen independent) and LN 24-hydroxylase activity in human prostatic carcinoma Cap (androgen dependent). Vitamin C induces these cells suggests new alternatives for the pharmaco- changes through production of hydrogen peroxide, logical treatment of advanced prostatic cancer and which in turn produces free radicals that damage the implies that chemoprevention strategies could also make use of this endocrine axis [24]. It has beenobserved that vitamin D and its analogoues inducecell cycle arrest and apoptosis in the premalignant Selenium
It is an important component of metalloenzymeglutathione peroxidase, which destroys peroxidase in Vitamin E
cytosol. It acts as a synergistic anti-oxidant withvitamin E. Epidemiological studies have shown that It occurs in the nature as a mixture of several closely the risk of cancer for patients with low serum selenium relative compounds called as tocopherols. It is an levels reported up to twice that of subjects with high important natural antioxodant and scavenger. Due to levels [19, 40]. A significantly low risk of developing its lypophilic character it accumulates in circulating prostate cancer has been observed in men receiving lipoproteins, cellular membranes and fat deposits, where it reacts very rapidly with molecular oxygenand free radicals. It acts as a scavenger for thesecompounds, protecting unsaturated fatty acids from Lycopene
peroxidation reaction and protects cellular respira-tion by stabilizing coenzyme-Q. Animal studies have Lycopene is a carotenoid which are found in high shown that dietary vit. E produces 30–60% inhibition levels in some fruits and vegetables (cooked or raw of induced carcinogenesis due to its ability to inhibit tomatoes and watermelon). Lycopene acts as an anti- synthesis of nitrosamine compounds. In human alpha- oxidant by preventing damage to DNA by protecting Tocopherol Bet-Carotene Cancer Prevention Study 2 -deoxy-guanosine against singlet oxygen damage.
(1995) showed that man receiving vit. E had a 34% It suppresses insulin like growth factor-1-stimulated lower incidence of carcinoma prostate [1, 36]. Eich- cell proliferation. An important study showed that holzer et al. (1996) in their study observed that men lycopene is found in very high concentration in with low plasma levels of vit. E had an increased risk the prostate, adrenal and testes. Lycopene reduced levels of serum protein thiol (an oxidative damagebiomolecular marker) levels among prostate cancerpatients [19].
Vitamin C
Prospective randomized controlled trials have shown lower prostate cancer risk in men with elevated Vitamin C is a six carbon organic acid with structural plasma lycopene levels. Research results presented similarity to glucose. It is a potent reducing (anti- at 90th annual meeting of American Association oxidant) in several hydroxylation reaction making it for Cancer Research (AACR) described the different capable of reducing compounds like molecular oxygen effects of lycopene like reduction in tumor size, and nitrates (scavenger). It inhibit malignant trans- lowering of S-PSA levels and reduction in grade of formation, decreases chromosomal damage in the cell [4]. Diets mainly comprising of fruits and vegetablesrich in vitamin C are associated with low incid-ence of cancer of oesophagus, stomach, colon, skin Dietary fat
A study by the American Cancer Society has shown This compound is again under scrutiny as it has been that obesity increased the risk of prostatic cancer [29].
observed that in male ACI/Seg rats, which spontan- Epidemiological studies done to compare different eously develop prostate cancer, the 5alpha-reductase populations around the world revealed the relation of inhibitor FK143 may, at specific doses, reduce the dietary fat and risk of prostate cancer [16]. Analysis incidence of spontaneously developing prostate cancer has revealed that mortality rate of prostate cancer is correlated with the estimated intake of dietary fat.
Essential fatty acids influence cellular proliferation, Miscellaneous compounds
tissue invasiveness, metastatic spread of tumors andimmune response as well as cell surface receptors [28].
Nonsteroidal anti-inflammatory drugs Long chain n-3 fatty acids have inhibitory effect andn-6 fatty acids have stimulatory effect. Likwise men Nonsteroidal anti-inflammatory drugs (NSAIDs) play with increased levels of cholesterol have more risk of potential roles in chemoprevention of colon cancer and others by inhibiting prostaglandin synthesis. Westernand northern blot analyses demonstrated that flufe-namic acid (FA) inhibited the androgen receptor (AR) Hormonal manipulation
expression at mRNA and protein levels when used onLNCaP cells, an androgen-responsive human prostate carcinoma cell line. Suppressed AR expression may bethe cause of FA-mediated inhibition of the androgen inducible gene expression. FA and other similar (HGPIN) is believed to be a precursor for prostatic NSAIDs may be potential candidates for chemo- prevention of human prostate cancer by modulating advancing age. Autopsy studies suggest that PIN mayprecede the development of prostatic adenocarcinoma by up to 10 years. Autopsy studies reveal thatHGPIN is found in association with cancer in 63% Ornithine decarboxylase (ODC), a rate-controlling to 94% of malignant and 25% to 43% of benign enzyme in the polyamine biosynthetic pathway, prostates [30]. As such, HGPIN is believed to be is overexpressed in prostate cancer (PCA) and marker of increased risk. This provides a potential opportunity for chemoprevention. Flutamide is one could be effective against prostate cancer. Green tea agent with potential activity and limited side effects polyphenols (GTPs) posses strong chemopreventive that may act to prevent or delay the onset of prostatic properties against a variety of animal tumor models adenocarcinoma in men with HGPIN. A clinical and in some human epidemiological studies. Similar trial is currently underway to assess the efficacy of effects of GTPs were observed in anchorage- independent growth assay of LNCaP cells wherepretreatment of the cells with GTP was found to result in dose-dependent inhibition of colony formation.
Similar effects of GTPs were observed in anchorage- In male Wistar-Unilever rats after experimentally independent growth assay of LNCaP cells where induction of prostate adenocarcinomas, it was seen pretreatment of the cells with GTP was found to result that nontoxic doses of DHEA confer significant in dose-dependent inhibition of colony formation protection against prostate carcinogenesis in rats. The [13]. In another study EGCG [(-)-epigallocatechin- efficacy of delayed administration of DHEA suggests 3-gallate], the major constituent of green tea, was that the compound confers protection against later examined to understand mechanisms of action. Effects stages of prostate cancer induction and can suppress of EGCG on the cell population were examined with the progression of existing preneoplastic lesions to growth assays, cell cycle analysis, and western blots for retinoblastoma protein (pRB). In each cell type, EGCG inhibited growth, with a decrease in efficacy Brooks JD, Weinstein M, Lin X et al. CG island methyla- as cells progressed from normal to cancer [17].
tion changes near the GSTP1 gene in prostatic intraepithelialneoplasia. Cancer Epidemiol Biomarkers Prev 1998; 7.
Diaz GD, Paraskeva C, Thomas MG et al. Apoptosis isinduced by the active metabolite of vitamin D3 and its Conclusion
analogue EB1089 in colorectal adenoma and carcinoma cells:Possible implications for prevention and therapy. Cancer Res2000; 60(8): 2304–2312.
Numerous studies implicate dietary and nutritional Eilchholzer M, Stahelin HB, Gey KF et al. Prediction of male factors in the onset and progression of prostate cancer mortality by plasma levels of interacting vitamins: 17- cancer. Hence, it is possible that bioactive compounds year follow-up of the prospective Basel study. Int J Cancer (anti-oxidants) like vits. A, D, C, and E, mineral Gupta S, Ahmad N, Mohan RR et al. Prostate cancer chemo- like selenium and carotenoids like lycopene can be prevention by green tea: In vitro and in vivo inhibition of a part of chemopreventive strategies for prostate testosterone-mediated induction of ornithine decarboxylase.
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The alpha-Tocopherol Bet-Carotene Cancer Prevention Study.
Address for correspondence: Dr. M.S. Ansari, MS, Mch, DipNB, The effect of vitamin E and beta-carotene on the incidence of 130-I Block, Sarojini Nagar, New Delhi, India lung cancer and other cancers in male smokers. New Engl J

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