ta mimi 2002

REVIEW

Prospects for chemoprevention of cancer

R . M . T A M I M I 1 , P . L A G I O U 1 , 2 , H . - O . A D A M I 1 , 3 & D . T R I C H O P O U L O S 1 , 2 , 3

From the 1Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA; 2Department of Hygiene and Epidemiology, University

of Athens Medical School, Goudi, Athens, Greece; and 3Department of Medical Epidemiology, Karolinska Institute, University of Stockholm,Stockholm, Sweden

Abstract. Tamimi RM, Lagiou P, Adami H-O,

Trichopoulos D (Harvard School of Public Health,Boston, MA, USA; University of Athens Medical

School, Goudi, Athens, Greece; and Karolinska

Institute, University of Stockholm, Stockholm, Swe-den). Prospects for chemoprevention of cancer

(Review). J Intern Med 2002; 251: 286–300.

The recent progress in molecular biology andpharmacology has increased the likelihood that

cancer prevention will rely increasingly on inter-

ventions collectively termed ‘chemoprevention’.Cancer chemoprevention is the use of agents to

inhibit, delay or reverse carcinogenesis. A number of

potential targets for chemoprevention have recently

been identified. Many classes of agents includingantioestrogens, anti-inflammatories, antioxidants

and other diet-derived agents have shown a great

deal of promise. In this review, we will begin bydescribing the general classes of chemopreventive

agents and the mechanisms by which these agents

act. We will then describe the opportunities thatpresently exist for chemoprevention of specific can-

cers.

Keywords: anti-inflammatories, antioestrogens,antioxidants, cancer, chemoprevention, diet-derived

agents.

Introduction

Cancer, currently the second leading cause of deathin the western world, may outrank cardiovascular

diseases in the US and other developed countries in afew decades [1–3]. The recent progress in molecular

biology and pharmacology has increased the likeli-

hood that cancer prevention, either primary orsecondary, will rely increasingly on interventions

collectively termed ‘chemoprevention’.

Cancer chemoprevention is the use of agents toinhibit, delay or reverse carcinogenesis. The pro-

gression towards invasive cancer is characterized by

accumulation of mutations and increased prolifer-ation. Because carcinogenesis is a multistage process

and often has a latency of many years or decades,

there is considerable opportunity for intervention.

Molecular advances have led to the identification of

genetic lesions and other cellular components,which may be involved in the initiation and

progression of malignancies, and constitute poten-tial targets for chemoprevention. As most cancers

are likely to be associated with mutagens and/or

mitogens, focusing on compounds that may inhibitor reverse either of the related processes may be

crucial in the search for chemotherapeutic agents.

Chemoprevention has obvious common elementswith chemotherapy, but also distinct differences.

Thus, chemoprevention focuses on reduction of

incidence and is related to classical epidemiology,whereas chemotherapy focuses on prognosis and is

related to clinical epidemiology. Chemotherapy can

Journal of Internal Medicine 2002; 251: 286–300

286 ª 2002 Blackwell Science Ltd

be either systemic or, in certain cases, localized,

whereas chemoprevention is almost always sys-

temic. In chemotherapy the outcome is generally ahigh frequency event (like death or metastasis),

whereas in chemoprevention it is usually of low

frequency (incident cancer cases); this is reflected inthe required sample size in the corresponding

studies. Last, chemotherapy is applied to seriously

ill patients, for whom side-effects, even serious ones,may be acceptable, whereas chemoprevention is

generally administered to healthy people for whom

serious side-effects are unacceptable.Several models have been developed to outline the

pathways through which carcinogenesis may occur.

These include the Vogelstein model for colon cancer[4], as well as models for cancer of the head and

neck [5, 6], brain [7], bladder [8, 9] and lung [5, 10].

Valid models of cancer progression facilitate theidentification of intermediate biomarkers. By serving

as surrogate end-points, such markers are pivotal in

identifying chemopreventive agents. The use of earlymarkers of carcinogenesis allows chemopreventive

studies to focus on stage arrest or reversion follow-ing treatment [11].

Many classes of agents have shown promise as

chemopreventive agents. These include antioestro-gens, anti-inflammatories and antioxidants, and

other diet derived agents. In this review, we will

begin by describing the general classes of chemo-preventive agents and the mechanisms by which

these agents act. We will then describe the oppor-

tunities that presently exist for chemoprevention ofspecific cancers.

Chemopreventive agents

Antioestrogens and antiandrogens

Sex steroid hormones have been implicated in the

aetiology of a number of cancers including breast,endometrium, prostate, testis, ovary, thyroid and

others [12]. These hormones are growth factors

favouring cell proliferation, thus increasing thepotential for mutations. Interruption of the hor-

monal stimulus is believed to slow the proliferation

of cells and the progression of hormone-relatedcancer. Therefore, antioestrogens, aromatase inhib-

itors and 5-a reductase inhibitors are obvious

candidates for chemoprevention of steroid-relatedcancers.

Tamoxifen and raloxifene are both selective

oestrogen receptor modulators (SERMs). These com-

pounds have different effects in different tissue types.In the breast, both of them act as oestrogen

antagonists, by inhibiting the proliferative effects of

oestrogens [13]. SERMs, however, can also act asoestrogen agonists in specific tissues by enhancing

the growth promoting effects of oestrogens [13];

thus, raloxifene is considered beneficial againstosteoporosis.

Studies of prostate biology have identified andro-

genic stimulation as a permissive factor for thedevelopment of both benign prostate hyperplasia

and cancer. Thus, factors involved in the produc-

tion, activation and transport of androgens havebeen considered potential targets for chemopreven-

tion. Dihydrotestosterone (DHT) is considered the

principal androgen. This has led to the hypothesisthat suppressing DHT synthesis may inhibit prostate

enlargement and possibly carcinogenesis. 5-a-reduc-

tase is the enzyme, which converts testosterone toDHT. Hence, inhibitors of this enzyme, such as

finasteride and turosteride, have a potential aschemopreventive agents.

Anti-inflammatories

It has long been suspected that inflammation is

intimately linked to carcinogenesis. Thus, agentswith anti-inflammatory properties, such as

nonsteroidal anti-inflammatory drugs (NSAIDs),

including aspirin, piroxicam and indomethacinare likely to exert chemopreventive action [14,

15]. A number of human observational studies

have supported the hypothesis that regular aspirinuse reduces the risk of colorectal cancer by

about 50% [16, 17]. Both in vitro and in vivo

models suggest that NSAIDs inhibit colon tumoursthrough induction of apoptosis, i.e. programmed

cell death [18].

Cyclooxygenases (COX-1 and 2) have been identi-fied as important enzymes necessary for the synthe-

sis of inflammatory prostaglandins from arachidonic

acid. Overexpression of COX-2 is believed to be anearly event in colon carcinogenesis and the devel-

opment of other epithelial tumours [19]. NSAIDs are

known to inhibit these enzymes. Moreover, selectiveinhibitors of COX-2 have been developed and these

may play a beneficial role in modulating carcino-

genic processes.

ª 2002 Blackwell Science Ltd Journal of Internal Medicine 251: 286–300

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R . M . T A M I M I et al.288

Diet-derived agents

Agents derived from dietary sources have an inher-ent appeal for chemoprevention aimed at healthy

populations, as they can be taken for long periods of

time with simple dietary modification and no

apparent health risk. Many diet-derived agents are

currently being evaluated for potential chemo-preventive activity. These agents, several with

antioxidant properties, will now be reviewed.

Fig. 1 Proposed chemopreventive agents and the postulated mechanism through which they may act. The Xs indicate the agent is

hypothesized to inhibit carcinogenesis either by blocking initiation, progression/proliferation or angiogenesis. The arrows indicate that the

agent is believed to divert the cell towards other pathways away from carcinogenesis such as apoptosis and differentiation. In addition, these agents are also postulated to inhibit angiogenesis.



Antioxidants

Antioxidants are compounds used by aerobicorganisms for protection against oxidative stress,

induced by free radicals and active oxygen species.

They exert their protective action either by suppres-sing the formation of free radicals or by scavenging

free radicals [20]. A wide range of biological effects,

established experimentally, may inhibit carcino-genesis. These include effects on tumour initiation,

promotion and progression, cell proliferation and

differentiation, as well as DNA repair, cell membranestability and immune function [20, 21]. Diet derived

antioxidants such as carotenoids, vitamins C and E

and selenium have received much attention aspotential cancer chemopreventive agents.

Carotenoids. Carotenoids are fat-soluble compoundsclassifiable as xanthophylls, carotenes or lycopene.

Over 600 carotenoids occur in nature and, amongst

them, the most commonly available in human diet isb-carotene. Carotenoids, found in large quantities in

green and yellow leafy vegetables, have in additionto antioxidant, other beneficial properties [21].

Moreover, these compounds are relatively nontoxic.

Observational epidemiologic studies are fairly con-sistent in indicating a protective effect of carotene-

rich vegetables, b-carotene, or in a few instances one

or more other carotenoids, on cancers of the lung,oesophagus, stomach, colorectum, cervix, orophar-

ynx and prostate [22–25]. Yet, it is unclear how

much of this effect could be attributed to replenish-ment of these vitamins in deficient populations [26,

27] or to confounding by other compounds with

cancer chemopreventive potential.Hopes that carotenoids could become a valuable

weapon against cancer, however, were dealt a blow

from the results of two major randomized trials thatfailed to demonstrate preventive effectiveness of

these compounds against lung cancer amongst

high-risk individuals, like elderly smokers [28, 29].These trials and other major chemoprevention trials

are summarized in Table 1.

Vitamin C. Vitamin C, a water-soluble vitamin, is an

important free radical scavenger in plasma and acts

to regenerate active vitamin E in lipid membranes.Vegetables, citrus fruits and tubers are good sources

of vitamin C. Although several different factors in

fruits and vegetables probably act jointly, the

epidemiologic and biochemical evidence indicate

an important role for vitamin C [30]. The evidence

for a protective effect of vitamin C is strong forcancer of the stomach, and upper aerodigestive

track and weaker for other forms of cancer [20, 21].

Vitamin E. Vitamin E, a fat-soluble vitamin, is the

major lipid-soluble antioxidant of the cell mem-

brane. It acts as a free-radical scavenger and inhibitsperoxidation [31]. It has been reported to block the

in vivo formation of N-nitroso compounds [32] and

suppress chemically induced tumours in experimen-tal animals [33]. a-Tocopherol is the most active

amongst the tocopherols and tocotrienols with

vitamin E activity. Vegetable oils, whole-wheatproducts and nuts are amongst the best sources of

vitamin E.

Overall, observational epidemiological studiessuggest a protective effect of vitamin E against

cancers of the lung [34, 35], colorectum [36] and

the cervix [37–39]. In the context of the a-Tocopherol, b-Carotene Cancer Prevention Study

(ATBC) randomized intervention study [40], aninverse association between vitamin E intake and

cancers of the lung, colorectum and prostate was

also reported.

Selenium. Selenium is a trace element and an

essential cofactor for the major antioxidant enzymeglutathione peroxidase, which catalyses the oxida-

tion of hydroperoxides [41]. Selenium is also in-

volved in cell signalling and immune responseprocesses [42], which may contribute to its cancer

chemopreventive potential. Selenium and vitamin E

may mutually compensate deficiency of each otherand act synergistically to inhibit carcinogenesis [43,

44]. The amount of selenium that appears in our

diet is determined by the selenium content of the soilin which fruits and vegetables are grown. Seafood,

liver and meat are also good sources of selenium.

In animal models, selenium has been shown to beantitumourigenic when administered at high doses

[45]. Ecological studies originally indicated that

there may be an inverse association between selen-ium levels and cancer overall, as well as cancer of

the breast, pancreas, ovary, colon, lung and cervix

and pancreas [46]. Results from analytical epidemi-ological studies remain inconclusive, with observa-

tional studies supportive of a protective role of

selenium against cancers of the lung, liver and



stomach, and one randomized controlled trial indi-

cating an inverse association of selenium with

cancers of the lung, colon and prostate [47, 48].

Flavonoids. Flavonoids are phenolic compounds

with anticarcinogenic [49, 50], tyrosine kinase[51, 52] and aromatase-inhibiting [53, 54] proper-

ties. Tea polyphenols, in particular, are strong

scavengers of superoxide, hydrogen peroxide, hy-droxy radicals and nitrogen oxides [55] and may

enhance the levels of antioxidant enzymes such as

catalase [56]. Flavonoids are found in fruits, vege-tables and tea leaves.

A number of animal studies have demonstrated

that catechins, the main flavonoids found in tealeaves, prevent induction of cancers of the lung [57],

the colon [58], the oesophagus [59, 60], the pancreas

[61, 62], the liver [63, 64] and the mammary gland[65, 66]. Observational studies in humans have

generated conflicting results, and long-term popula-

tion studies are now being considered [67–69].

Isoflavones. Isoflavones, found mainly in soy prod-ucts, are structural isomers of flavonoids and share

biological properties with them. They have antioes-

trogenic effects [70], and thus could act as chemo-preventive agents in hormone dependent cancers.

Genistein, a prominent isoflavone in soy products

has also been shown to induce apoptosis in vivo [71].Epidemiologic studies suggest that women and men

in Asian countries consuming high amounts of soy

products may be at lower risk for breast cancer andprostate cancer, respectively [72].

Curcumin. Curcumin is a plant phenol widely usedas a spice (curry) and food-colouring agent. In vivo

and in vitro studies have demonstrated that it may

prevent initiation of DNA damage and is involved inantipromotion mechanisms such as apoptosis [73,

74]. A number of animal studies have shown that

curcumin is effective in inhibiting carcinogenesis inthe skin [75, 76], colon [77, 78], oral cavity [79],

stomach [77, 80] and mammary gland [81, 82].

Results from human trials have not been reported.

Other diet-derived agents

Retinoids. The best known retinoid is vitamin A or

retinol, found in foods of animal origin, such as liver,

milk and dairy products, egg yolk and fish liver oils,

but there are also several synthetic compounds [21].

Retinoids are required for the maintenance of

normal cell growth and differentiation. In contrastto carotenoids, they act primarily in the postinitia-

tion phases of promotion and progression [20].

Retinoids do have known limitations, in that theymay be toxic at therapeutic levels and would require

lifetime use for protection [83, 84].

Various retinoids have been shown to suppress orreverse epithelial carcinogenesis at several sites in

many animal systems. Several chemoprevention

trials have been undertaken or are ongoing. Themost promising results have been reported for oral

carcinogenesis [85, 86].

Vitamin D. 1,25-Dihydroxyvitamin D3 (1,25-D3) is

the active form of the fat-soluble vitamin D. Major

dietary sources of vitamin D include liver, fatty salt-water fish and eggs. Vitamin D inhibits proliferation

and DNA synthesis, alters expression of several

oncogenes, reduces lipid peroxidation and angio-genesis and induces differentiation [87].

Epidemiologic studies support an inverse associ-ation between vitamin D intake and colorectal

cancer risk [21] and have also shown that vitamin

D3 deficiency [88], and low plasma levels of 1,25-D3[89, 90] increase the risk for prostate cancer. The

overall evidence, however, remains insufficient.

Folic acid. Folic acid is abundant in many of the

fruits and vegetables that are rich in carotenoids.

Together with vitamin B12, methionine and cho-line, it is involved in methyl group metabolism.

Much of the basic cancer research has focused on

DNA methylation, and hypomethylation has beenassociated with DNA abnormalities [91]. An inverse

association between dietary folate intake and aden-

omatous polyps or colorectal cancer has beenreported in both case–control [92] and cohort

studies [93].

Chemoprevention at specific cancer sites

Oral cavity and other head and neck tumours

Head and neck cancers account for 2–3% of allcancers worldwide [94, 95]. Most head and neck

cancers are found in the oral cavity and more than

two-thirds of oral cancer cases can be attributed totobacco, either alone or in concert with alcohol [3].



Cancers of the head and neck are almost always

preceded by precursor lesions, such as leukoplakia,

which can easily be visualized with examination ofthe oral cavity. Precancerous lesions have been

useful surrogate markers for the effect of chemopre-

ventive agents.Early studies looking at retinoids and b-carotene

indicated that these agents have considerable

potential for chemoprevention of oral cancer [83,85, 96]. Enthusiasm, however, has been curtailed by

a number of factors, such as variability in the

reported efficacy of the evaluated agents, inability todistinguish between replenishment effects in defici-

ent populations and monotonic exposure response

across various dose levels [27], and difficulty toaccommodate the required long-term administration

of the compounds, particularly in view of their

limited but established toxicity [83, 84]. Currently, anumber of synthetic retinoic acid derivatives, vita-

min E and NSAIDs are being studied to determine

efficacy and safety.

Breast

Epidemiologic studies have identified a number of

component causes of breast cancer, most of whichare either difficult to modify (reproductive variables),

or require drastic to ethically questionable interven-

tions (preventive mastectomy in breast cancer genecarriers). For this reason, scientific interest has

shifted to chemoprevention as a means of primary

prevention of breast cancer.After observing a reduction in risk of contralateral

breast cancer amongst women with tamoxifen

treatment, it was suggested that tamoxifen mayhave the potential to prevent breast cancer [97, 98].

Results concerning the efficacy of tamoxifen as a

chemopreventive agent for breast cancer have beenreported from three randomized trials (summarized

in Table 1) [99–101]. Cuzick et al. conducted a

meta-analyses of the available data and found thatthe results are compatible with a 42% reduction in

incidence of breast cancer, which is restricted to

oestrogen receptor positive cases [102]. Anincreased risk for endometrial cancer, stroke and

deep vein thrombosis are listed amongst the poten-

tial side-effects of tamoxifen [99, 103].Raloxifene a newer SERM intended for prevention

of osteoporosis may be at least as effective as

tamoxifen in preventing breast cancer and, unlike

tamoxifen, does not appear to increase the risk for

endometrial cancer. Yet it appears to share with

tamoxifen the side-effect of thromboembolic events[102, 104].

Finretidine, a vitamin A analogue, has also been

examined as a chemopreventive agent for breastcancer. A recent randomized control trial detected

no difference between treated and untreated women,

although data suggest a possible benefit in pre-menopausal women [105].

Stomach

Although the rates of stomach cancer have been

decreasing, it remains the second most commoncancer worldwide, after lung cancer. Asian countries

have high incidence rates of gastric cancer [94].

Analytical epidemiological studies have highlightedseveral important risk factors including diets poor in

fresh fruits and vegetables, and high in salt [106].

Infection with Helicobacter pylori is thought to play akey role in the majority of gastric cancer cases [107].

The multifactorial nature of gastric cancer providesdiverse opportunities for intervention. In a number

of studies, increased intakes or plasma levels of

b-carotene and vitamin C were inversely associatedwith gastric cancer. The Linxian study (summarized

in Table 1) in China is a randomized control trial to

study the effect of supplementation with multiplemicronutrients on the incidence of cancer. This study

revealed a 21% decrease in gastric cancer mortality

amongst participants receiving b-carotene, vitamin Eand selenium [108]. As there are limited methods of

screening for gastric cancer and eradication of H.

pylori infection is currently unrealistic, chemopre-vention, as well as salt reduction, may represent

effective ways for controlling gastric cancer.

Liver

Most cases of primary liver cancer are hepatocellularcarcinomas (HCC). The majority of cases of HCC in

Africa and Asia are linked to chronic infection with

hepatitis B (HBV) and/or hepatitis C (HCV) virus andperhaps to aflatoxin contamination of foods [109,

110]. In economically developed countries, how-

ever, alcohol drinking and tobacco smoking may beresponsible for most cases, although in about 50% of

them no obvious cause is epidemiologically identi-

fiable [111, 112]. Evidence concerning antioxidants



in the diet and HCC is inconsistent [113, 114].

Although vaccination against HBV and public

health measures to reduce infection by HCV areobvious priorities in Asian and African countries,

the size of the problem in these countries creates

room for chemopreventive interventions.Oltipraz [5-(2-pyrazinyl)-4 methyl-1,2 dithiole-3-

thione] is a single dose agent that affects the meta-

bolism of aflatoxin and reduces the number ofaflatoxin DNA adducts in animal models. A random-

ized trial of Oltipraz in Qidong, China, observed a

reduction of adduct levels in subjects on the treatmentarm, with minimal adverse effects [115]. There are

also studies exploring the effect of supplementation

with curcumin, green tea and herbs or selenium in thechemoprevention of liver cancer [116].

Oesophagus

Although oesophageal cancer is uncommon in most

parts of the world, its fatality is very high. For bothsquamous cell carcinoma (SCC) and adenocarcino-

ma, alcohol and tobacco play an important aetio-logic role in developed countries, although additional

important factors are likely to play an aetiological role

in adenocarcinoma [117]. In developing countries,however, diet, and particularly dietary deficiencies

are also implicated and there is considerable evi-

dence that consumption of fruits and vegetablesreduces the risk of oesophageal cancer of any type in

most populations [118].

Randomized chemoprevention trials undertakenin areas of China with high incidence of oesophageal

cancer have indicated that vitamin and mineral

supplementation convey some protection againstoesophageal cancer and related precancerous lesions

[119, 120]. However, these results were not stri-

king, and may not be generalizable because thestudy population groups were nutritionally deficient

and did not allow the identification of the most

important micronutrient, because multivitamin andmineral supplements were used. Candidate micro-

nutrients for oesophageal cancer chemoprevention

include b-carotene, vitamin C, retinol, riboflavin orzinc [119, 120].

Lung

Lung cancer is the leading cause of cancer related

deaths globally and tobacco smoking is by far the

most important risk factor [121]. The limited success

of both screening and treatment of lung cancer

made lung cancer an early target for chemopreven-tion trials. The original driving force to use b-caro-

tene as a chemopreventive agent came largely from

epidemiologic studies, which consistently suggestedthat people consuming diets rich in fruits and

vegetables are at a reduced risk of developing many

types of cancers, including lung cancer. Althoughthere was little direct evidence to support the

hypothesis that b-carotene was the critical agent

in fruits and vegetables, there was nonetheless agreat deal of optimism that b-carotene was going to

be the ‘magic bullet’ against cancer.

The Carotene and Retinol Efficay Trial (CARET)and the ATBC study are two large, randomized,

double blind studies specifically designed to deter-

mine if b-carotene, other antioxidants or retinolwould reduce the incidence of lung cancer in high

risk populations (see Table 1) [28, 29, 40, 122]. The

hopes were dashed, when both trials reported aslight increase – rather than a decrease – of lung

cancer incidence in the b-carotene arms.

Skin

Skin cancer is by far the most common type of

cancer, having a substantial impact on morbidity

and health care resources [123], accounting forapproximately 40% of all diagnosed cancers in the

US [124]. The most promising preventative agents

to date have been sunscreens.In skin tumourigenesis models, ultraviolet radi-

ation acts as a complete carcinogen [125]. Ultraviolet

exposure of normal skin can cause DNA thyminedimers, or single strand breaks, which may result in

permanent mutations maintained through DNA

replication [126–128]. In this model, the promotionfrom initiated cells into a preneoplastic state may take

10 years or longer. Well-described signal transduc-

tion pathways during this long promotion phase,provide potential targets for chemoprevention.

In some epidemiologic studies, some forms of tea

have been associated with a decreased risk of cancer[129]. Polyphenols in green tea have antimutagenic

and antitumour activities [130, 131]. Furthermore,

in animal studies, epigallocatechin gallate (EGCG),the most abundant polyphenol in green tea, reduced

the incidence of ultraviolet light induced skin

tumours [129, 132].



It has been suggested that oral vitamin A may have

a role in skin cancer chemoprevention. One double

blind randomized study of retinol found a 32%reduction in risk of developing SCCs compared with

placebo, without significant toxicity [133]. There are

a number of mechanisms by which retinoids arebelieved to act. In the skin, retinoids promote cellular

differentiation, may increase epidermal thickness

thereby decreasing ultraviolet transmission orthrough immunoregulatory functions [134, 135].

Prostate

Migration studies have shown that men who move

from countries of low incidence to countries of highincidence have an increase in prostate cancer [136]

and have, thus, implicated environmental factors in

the role of stimulating progression of latent micro-focal cancer to clinical disease.

There is epidemiologic evidence that nutritional

factors, such as meat, dairy products, and saturatedfat are associated with an increased risk, whilst

fruits and vegetables, tomatoes, and foods high inselenium and vitamin E have been associated with

reduced risk [21, 137].

Studies of prostate biology have identified long-term androgenic stimulation as a key component of

prostate carcinogenesis. For this reason, genes

involved in the production, activation and transportof androgens have been considered potential targets

for chemoprevention. DHT has been implicated as

the principal androgen responsible for hyperplasticgrowth of the prostate. This has led to the hypothesis

that suppressing DHT synthesis may inhibit prostate

carcinogenesis. 5-a-reductase is the enzyme, whichconverts testosterone to DHT. Hence, inhibitors of

this enzyme, such as finasteride and turosteride, are

plausible agents for chemoprevention.Animal studies using 5-a-reductase inhibitors

have been promising, demonstrating that these

agents are capable of preventing or slowing thegrowth of prostate cancer, as well as, preventing

prostate pathology [138, 139]. Finasteride has been

approved for the treatment of benign prostatichyperplasia by many regulatory agencies. Overall,

it is considered to have an acceptable safety profile,

but impotence and loss of libido are reasons forconcern [140].

There is evidence from randomized trials that

selenium and vitamin E intake may convey some

protection against prostate cancer. Subjects in the

ATBC study randomized to vitamin E supplements

showed a 33% reduction of prostate cancer inci-dence [122, 141]. The serendipitous findings of this

study and the selenium studies [48, 142] have

prompted the US National Cancer Institute to designa trial entitled ‘SELECT’. The recently initiated trial

will randomize men to selenium, vitamin E, both

selenium and vitamin E, or placebo and will look atprostate, lung and colorectal cancers as its primary

outcomes [143].

Data from epidemiologic and animal studies sug-gest that vitamin D may also be chemopreventive in

prostate cancer. Newly developed nontoxic vitamin

D3 analogues, showing antiproliferative effects onprostate cells [144], are currently being considered.

Large bowel

Colorectal cancer is one of the most common

malignancies in developed countries with a relat-ively high fatality that depends critically on the

stage of disease at diagnosis [145]. The molecularchanges involved in colorectal tumourigenesis have

been well described by Vogelstein and others [146].

Prevention of colorectal cancer can potentially occuranywhere along this multistep process. There is

convincing evidence that colon cancer arises from

adenomas with specific factors involved in thedevelopment of adenomas and further progression

to invasive cancer. A number of studies have

focused not only on the primary prevention of, butalso on the secondary prevention of adenoma

recurrence and growth.

Epidemiologic studies have indicated that theconsumption of fruits and vegetables prevents

against colon cancer [21, 137]. Folate, a micro-

nutrient highly abundant in fruits and vegetables,has gained a great deal of attention in the preven-

tion of colorectal cancer [147, 148]. It appears that

the benefit is greater amongst those who obtain theirfolate from supplements [149, 150]. In the Nurses’

Health Study, supplementation of folic acid, primarily

from multivitamin use, was protective against coloncancer and became statistically significant after

15 years of use, suggesting that folate may act

early in the carcinogenic process [150].Diets high in red meat and animal fat consump-

tion have been associated with an increased risk of

colorectal cancer [21, 137]. Whilst the exact



mechanism is still unclear these foods may increase

the production of secondary bile acids [151].

Calcium is hypothesized to prevent carcinogenesisin the colon by either binding bile acids and/or fatty

acids in the lumen or by having a direct inhibitory

effect on the proliferation of the epithelial cells inthe colon. Animal models support this hypothesis

and the majority of epidemiologic studies provide

some modest support for an inverse relationshipbetween the intake of calcium and colon adenomas

as well as colorectal cancer [152–154]. Recently, a

randomized control study assessed the efficacy ofcalcium supplementation on the risk of new colon

adenoma formation amongst individuals with a

history of adenomas [155]. Endoscopic examina-tions conducted after 1 and 4 years from the

initiations of the study found that those on the

treatment arm (3 g of calcium carbonate daily)compared with those on placebo had a reduced

incidence of adenomas apparent after just 1 year of

supplementation.Nonsteroidal anti-inflammatory drugs have been

widely studied because there are a number ofmechanisms through which these agents might

prevent colon cancer. Animal studies have provided

strong evidence, showing a 90% reduction in thenumber of adenomas [156] and a 52% reduction in

the total volume of colon tumours [78, 157]. These,

as well as molecular and epidemiological studiessupport the idea that NSAIDs have their preventa-

tive function early in the carcinogenic process.

Specifically, a number of case–control studies havefound a 40–50% reduction in colon cancer inci-

dence amongst patients taking aspirin regularly

[158, 159]. In contrast, the Physicians’ HealthStudy, a randomized control trial, did not find any

protective effect of low dose aspirin use on incidence

of colorectal cancer [160].Although the mortality rates from colorectal

cancer have been decreasing during the past two

decades, this decrease has been greater amongstwomen. One hypothesis to explain this is the

increased use of hormone replacement therapy

(HRT) amongst women. There are a number ofproposed mechanisms by which oestrogens may

prevent colorectal cancer. These include decreasing

the production of secondary bile acids, and reducingthe production of insulin growth factor I (IGF1)

[161]. Both the Cancer Prevention Study and the

Nurses’ Health Study also observed a significant

protection from colon cancers amongst current

users of HRT [162, 163]. The protective effect in

the Nurses’ Study was limited to those currentlyusing therapy and disappeared 5 years after stop-

ping use, which is supported by case–control studies

[164, 165]. This information, along with theproposed mechanism of action, supports the idea

that oestrogens have a late effect in colorectal

carcinogenesis.Epidemiologic studies have provided modest sup-

port of a protective role of fibre against colon

cancer [21, 137]. However, two large randomizedcontrol trials evaluating the effect of high fibre diets

amongst individuals with history of adenomas

failed to provide evidence of a protective effect[166, 167].

Conclusion

Chemoprevention is an attractive concept and may

represent a priority area for the utilization and

exploitation of our rapidly increasing understandingof the molecular processes involved in carcino-

genesis. In this context, it is quite possible that

genetic polymorphisms will be used to identifygroups that would benefit most from chemopreven-

tive interventions. There are, however, serious

constraints in the identification and subsequentimplementation of chemopreventive interventions.

Most important amongst these is the fact that

chemoprevention has a long latency, which makesit difficult to document effective interventions, as the

later may have to depend on two or more cycles of

randomized intervention trials.

References

1 Devesa SS, Blot WJ, Stone BJ, Miller BA, Tarone RE,

Fraumeni JF Jr. Recent cancer trends in the United States.

J Natl Cancer Inst 1995; 87: 175–82.2 Oliveria SA, Christos PJ, Berwick M. The role of epidemiology

in cancer prevention. Proc Soc Exp Biol Med 1997; 216:

142–50.3 Adami HO, Hunter D, Trichopoulos D. Textbook of Cancer

Epidemiology. New York, USA: Oxford University Press (in

press).

4 Fearon ER, Vogelstein B. A genetic model for colorectaltumorigenesis. Cell 1990; 61: 759–67.

5 Thiberville L, Payne P, Vielkinds J et al. Evidence of cumu-

lative gene losses with progression of premalignant epithelial

lesions to carcinoma of the bronchus. Cancer Res 1995; 55:5133–9.



6 Califano J, van der Riet P, Westra W et al. Genetic progres-

sion model for head and neck cancer: implications for field

cancerization. Cancer Res 1996; 56: 2488–92.

7 Sidransky D, Mikkelsen T, Schwechheimer K, Rosenblum ML,Cavanee W, Vogelstein B. Clonal expansion of p53 mutant

cells is associated with brain tumour progression. Nature

1992; 355: 846–7.

8 Rosin MP, Cairns P, Epstein JI, Schoenberg MP, Sidransky D.Partial allelotype of carcinoma in situ of the human bladder.

Cancer Res 1995; 55: 5213–6.

9 Mao L, Schoenberg MP, Scicchitano M et al. Moleculardetection of primary bladder cancer by microsatellite ana-

lysis. Science 1996; 271: 659–62.

10 Kishimoto Y, Sugio K, Hung JY et al. Allele-specific loss in

chromosome 9p loci in preneoplastic lesions accompanyingnon-small-cell lung cancers. J Natl Cancer Inst 1995; 87:

1224–9.

11 Kelloff GJ, Crowell JA, Steele VE et al. Progress in cancer

chemoprevention: development of diet-derived chemopreven-tive agents. J Nutr 2000; 130: 467S–471S.

12 Henderson BE, Feigelson HS. Hormonal carcinogenesis.

Carcinogenesis 2000; 21: 427–33.13 Osborne CK, Zhao H, Fuqua SA. Selective estrogen receptor

modulators: structure, function, and clinical use. J Clin Oncol

2000; 18: 3172–86.

14 Kelloff GJ, Boone CW, Steele VE et al. Mechanistic consider-ations in chemopreventive drug development. J Cell Biochem;

1994; 20 (Suppl.): 1–24.

15 IARC. IARC Handbooks of Cancer Prevention: Non-Steroidal

Anti-Inflammatory Drugs, Vol. 1. Lyon, France: IARC Scien-tific Publishers, 1997.

16 Kune GA, Kune S, Watson LF. Colorectal cancer risk, chronic

illnesses, operations, and medications: case–control resultsfrom the Melbourne Colorectal Cancer Study. Cancer Res

1988; 48: 4399–404.

17 Giovannucci E, Egan KM, Hunter DJ et al. Aspirin and the

risk of colorectal cancer in women. N Engl J Med 1995; 333:609–14.

18 Ahnen DJ. Colon cancer prevention by NSAIDs. What is the

mechanism of action? Eur J Surg 1998; 582 (Suppl.): 111–4.

19 Prescott SM, Fitzpatrick FA. Cyclooxygenase-2 and carcino-genesis. Biochim Biophys Acta 2000; 1470: M69–78.

20 Papas A. Antioxidant Status, Diet, Nutrition and Health. Boca

Raton, FL: CRC Press, 1999.

21 World Cancer Research Fund and American Institute forCancer Research. Food, Nutrition and the Prevention of Cancer:

a Global Perspective. Washington, DC: World Cancer Research

Fund and American Institute for Cancer Research, 1997.22 Willett WC. Vitamin A and lung cancer. Nutr Rev 1990; 48:

201–11.

23 Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. I.

Epidemiology. Cancer Causes Control 1991; 2: 325–57.24 van Poppel G, Goldbohm RA. Epidemiologic evidence for

beta-carotene and cancer prevention. Am J Clin Nutr 1995;

62 (Suppl.): 1393S–1402S.

25 Ziegler RG, Mayne ST, Swanson CA. Nutrition and lungcancer. Cancer Causes Control 1996; 7: 157–77.

26 Stich HF, Rosin MP, Hornby AP, Mathew B, Sankara-

narayanan R, Nair MK. Remission of oral leukoplakias andmicronuclei in tobacco/betel quid chewers treated with beta-

carotene and with beta-carotene plus vitamin A. Int J Cancer

1988; 42: 195–9.

27 Zaridze D, Evstifeeva T, Boyle P. Chemoprevention of oral

leukoplakia and chronic esophagitis in an area of high

incidence of oral and esophageal cancer. Ann Epidmiol 1993;

3: 225–34.28 Omenn GS, Goodman GE, Thornquist MD et al. Risk factors

for lung cancer and for intervention effects in CARET, the

Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst

1996a; 88: 1550–9.29 Omenn GS, Goodman GE, Thornquist MD et al. Effects of

a combination of beta-carotene and vitamin A on lung

cancer and cardiovascular disease. N Engl J Med 1996b; 334:1150–5.

30 Block G. Epidemiologic evidence regarding vitamin C and

cancer. Am J Clin Nutr 1991; 54: 1310S–1314S.

31 Burton GW, Cheeseman KH, Doba T, Ingold KU, Slater TF.Vitamin E as an antioxidant in vitro and in vivo. Ciba Found

Symp 1983; 101: 4–18.

32 Mirvish SS. Effects of vitamins C and E on N-nitroso

compound formation, carcinogenesis, and cancer. Cancer1986; 58 (Suppl.): 1842–50.

33 Cook MG, McNamara P. Effect of dietary vitamin E on

dimethylhydrazine-induced colonic tumors in mice. CancerRes 1980; 40: 1329–31.

34 Knekt P, Jarvinen R, Seppanen R et al. Dietary antioxidants

and the risk of lung cancer. Am J Epidemiol 1991; 134:

471–9.35 Comstock GW, Bush TL, Helzlsouer K. Serum retinol, beta-

carotene, vitamin E, and selenium as related to subse-

quent cancer of specific sites. Am J Epidemiol 1992; 135:

115–21.36 Longnecker MP, Martin-Moreno JM, Knekt P et al. Serum

alpha-tocopherol concentration in relation to subsequent

colorectal cancer: pooled data from five cohorts. J Natl CancerInst 1992; 84: 430–5.

37 Verreault R, Chu J, Mandelson M, Shy K. Case-control study

of diet and invasive cervical cancer. Int J Cancer 1989; 43:

1050–4.38 Ziegler RG, Brinton LA, Hamman RF et al. Diet and the risk of

invasive cervical cancer among white women in the United

States. Am J Epidemiol 1990; 132: 432–45.

39 Ziegler RG, Jones CJ, Brinton LA et al. Diet and the risk ofin situ cervical cancer among white women in the United

States. Cancer Causes Control 1991; 2: 17–29.

40 The ATBC Cancer Prevention Study Group. The effect of vitamin

E and beta-carotene on the incidence of lung cancer andother cancers in male smokers. N Engl J Med 1994; 330:

1029–35.

41 Hoekstra WG. Biochemical function of selenium and itsrelation to vitamin E. Fed Proc 1975; 34: 2083–9.

42 Medina D. Mechanisms of selenium inhibition of

tumorigenesis. Adv Exp Med Biol 1986; 206: 465–72.

43 Flohe L, Beckmann R, Girtz H, Loschen G. Oxygen-centeredfree radicals as mediators of inflammation. In: Sies H, ed.

Oxidative Stress. New York: Academic press, 1985.

44 Parker RS. Dietary and biochemical aspects of vitamin E. Adv

Food Nutr Res 1989; 33: 157–232.45 Combs GF Jr. Selenium and cancer. In: Wang Z, ed.

Biochemistry and Molecular Biology of Selenium. Beijing,

China: Chinese Academy of Science, 1995.46 Clark LC, Cantor KP, Allaway WH. Selenium in forage crops

and cancer mortality in forage crops and cancer mortality in

US counties. Arch Environ Health 1991; 46: 37–42.



47 Rayman MP. The importance of selenium to human health.

Lancet 2000; 356: 233–41.

48 Clark LC, Combs GF Jr, Turnbull BW et al. Effects of selenium

supplementation for cancer prevention in patients withcarcinoma of the skin. A randomized controlled trial.

Nutritional Prevention of Cancer Study Group. JAMA

1996; 276: 1957–63.

49 Verma AK, Johnson JA, Gould MN, Tanner MA. Inhibition of7,12-dimethylbenz(a)anthracene- and N-nitrosomethylurea-

induced rat mammary cancer by dietary flavonol quercetin.

Cancer Res 1988; 48: 5754–8.50 Lee KW, Wang HJ, Murphy PA, Hendrich S. Soybean

isoflavone extract suppresses early but not later promotion

of hepatocarcinogenesis by phenobarbital in female rat liver.

Nutr Cancer 1995; 24: 267–78.51 Levy J, Teuerstein I, Marbach M, Radian S, Sharoni Y.

Tyrosine protein kinase activity in the DMBA-induced rat

mammary tumor: inhibition by quercetin. Biochem Biophys

Res Commun 1984; 123: 1227–33.52 Akiyama T, Ishida J, Nakagawa S et al. Genistein, a specific

inhibitor of tyrosine-specific protein kinases. J Biol Chem

1987; 262: 5592–5.53 Adlercreutz H, Bannwart C, Wahalasnm K et al. Inhibition of

human aromatase by mammalian lignans and isoflavonoid

phytoestrogens. J Steroid Biochem Mol Biol 1993; 44: 147–

53.54 Wang C, Makela T, Hase T, Adlercreutz H, Kurzer MS.

Lignans and flavonoids inhibit aromatase enzyme in human

preadipocytes. J Steroid Biochem Mol Biol 1994; 50:

205–12.55 Chen CW, Ho CT. Antioxidant properties of polyphenols

extracted from green and black teas. J Food Lipids 1994; 2:

35–46.56 Khan SG, Katiyar SK, Agarwal R, Mukhtar H. Enhancement

of antioxidant and phase II enzyme by oral feeding of green

tea polyphenols in drinking water to SKH-1 hairless mice:

possible role in cancer chemoprevention. Cancer Res 1992;52: 4050–2.

57 Witschi H, Espiritu IYuM, Willitis NH. The effects of

phenethyl isothiocynate, N-acetylcysteine and green tea on

tobacco smoke induced lung tumors in strain A/J mice.Carcinogenesis 1998; 19: 1789–94.

58 Hirose M, Hoshiya T, Akagi K, Takahashi S, Hara Y, Ito N.

Effects of green tea catechins in a rat multi-organ carcino-

genesis model. Carcinogenesis 1993; 14: 1549–53.59 Han C, Xu Y. The effect of Chinese tea on the occurrence of

esophageal tumor induced by N-nitrosomethylbenzylamine

in rats. Biomed Environ Sci 1990; 3: 35–42.60 Chen J. The effect of Chinese tea on the occurrence of

esophageal tumors induced by N-nitrosomethylbenzylamine

in rats. Prev Med 1992; 21: 385–91.

61 Harada N, Takabayashi F, Oguni I, Hara Y. Anti-promotioneffect of green tea extracts on pancreatic cancer in golden

hamsters induced by N-nitroso-bis(2-oxopropyl) amine. Int

Symp Tea Sci Jpn 1991; 200–204.

62 Majima T, Tsutsumi M, Nishino H, Tsunoda T, Konishi Y.Inhibitory effects of beta-carotene, palm carotene, and green

tea polyphenols on pancreatic carcinogenesis initiated by

N-nitrosobis(2-oxopropyl) amine in Syrian golden hamsters.Pancreas 1998; 16: 13–8.

63 Chen ZY, Yan RQ, Qin GZ, Qin LL. Effect of six edible plants

on the development of AFB1-induced gamma-glutamyltrans-

peptidase positive hepatocyte foci in rats. Chung-Hua Chung

Liu Tsa Chih [Chin J Oncol] (in Chinese) 1987; 9: 109–11.

64 Qin G, Gopalan-Kriczky P, Su J, Ning Y, Lotlikar PD.

Inhibition of aflatoxin B1-induced initiation of hepatocarci-nogenesis in the rat by green tea. Cancer Lett 1997; 112:

149–54.

65 Hirose M, Hoshiya T, Akagi K, Futakuchi M, Ito N. Inhibition

of mammary gland carcinogenesis by green tea catechinsand other naturally occurring antioxidants in female Spra-

gue–Dawley rats pretreated with 7,12-dimethyl-

benz[alpha]anthracene. Cancer Lett 1994; 83: 149–56.66 Tanaka H, Hirose M, Kawabe M et al. Post-initiation inhib-

itory effects of green tea catechins on 7,12-dimethyl-

benz[a]anthracene-induced mammary gland carcinogenesis

in female Sprague–Dawley rats. Cancer Lett 1997; 116: 47–52.

67 Agarwal R, Mukhtar H. Cancer chemoprevention by po-

lyphenols in green tea and artichoke. Adv Exp Med Biol 1996;

401: 35–50.68 Blot WJ, Chow WH, McLaughlin JK. Tea and cancer: a review

of the epidemiologic evidence. Eur J Cancer Prev 1996; 5: 425–

38.69 The Indian–US Head and Neck Cancer Cooperative Group.

Green tea and leukoplakia. Am J Surg 1997; 174: 552–5.

70 Farmakalidis E, Hathcock JN, Murphy PA. Oestrogenic

potency of genistin and daidzin in mice. Food Chem Toxicol1985; 23: 741–5.

71 Wei H, Wei L, Frenkel K, Bowen R, Barnes S. Inhibition of

tumor promoter-induced hydrogen peroxide formation

in vitro and in vivo by genistein. Nutr Cancer 1993; 20: 1–12.72 Messina MJ. Legumes and soybeans: overview of their

nutritional profiles and health effects. Am J Clin Nutr 1999;

70 (Suppl.): 439S–450S.73 Bielak-Zmijewska A, Koronkiewicz M, Skierski J, Piwocka K,

Radziszewska E, Sikora E. Effect of curcumin on the apoptosis

of rodent and human nonproliferating and proliferating

lymphoid cells. Nutr Cancer 2000; 38: 131–8.74 Collett GP, Robson CN, Mathers JC, Campbell FC. Curcumin

modifies Apc (min) apoptosis resistance and inhibits 2-amino

1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induced tu-

mour formation in Apc (min) mice. Carcinogenesis 2001; 22:821–5.

75 Huang MT, Smart RC, Wong CQ, Conney AH. Inhibitory

effect of curcumin, chlorogenic acid, caffeic acid, and

ferulic acid on tumor promotion in mouse skin by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 1988; 48:

5941–6.

76 Huang MT, Newmark HL, Frenkel K. Inhibitory effects ofcurcumin on tumorigenesis in mice. J Cell Biochem 1997; 27

(Suppl.): 26–34.

77 Huang MT, Lou YR, Ma W, Newmark HL, Reuhl KR, Conney

AH. Inhibitory effects of dietary curcumin on forestomach,duodenal, and colon carcinogenesis in mice. Cancer Res

1994; 54: 5841–7.

78 Rao CV, Rivenson A, Simi B et al. Chemoprevention of colon

carcinogenesis by sulindac, a nonsteroidal anti-inflammatoryagent. Cancer Res 1995; 55: 1464–72.

79 Tanaka T, Makita H, Ohnishi M et al. Chemoprevention of

4-nitroquinoline 1-oxide-induced oral carcinogenesis bydietary curcumin and hesperidin: comparison with the

protective effect of beta-carotene. Cancer Res 1994; 54:

4653–9.



80 Singh SV, Hu X, Srivastava SK et al. Mechanism of inhibition

of benzo[a]pyrene-induced forestomach cancer in mice by

dietary curcumin. Carcinogenesis 1998; 19: 1357–60.

81 Pereira MA, Grubbs CJ, Barnes LH et al. Effects of thephytochemicals, curcumin and quercetin, upon azoxyme-

thane-induced colon cancer and 7,12-dimethylbenz[a]an-

thracene-induced mammary cancer in rats. Carcinogenesis

1996; 17: 1305–11.82 Singletary K, MacDonald C, Iovinelli M, Fisher C, Wallig M.

Effect of the beta-diketones diferuloylmethane (curcumin)

and dibenzoylmethane on rat mammary DNA adducts andtumors induced by 7,12-dimethylbenz[a]anthracene. Carci-

nogenesis 1998; 19: 1039–43.

83 Hong WK, Endicott J, Itri LM et al. 13-cis-retinoic acid

in the treatment of oral leukoplakia. N Engl J Med 1986; 315:1501–5.

84 Lippman SM, Kessler JF, Meyskens FL Jr. Retinoids as

preventive ad therapeutic anticancer agents (Part 1). Cancer

Treatment Rep 1987; 71: 391–405.85 Chiesa F, Tradati N, Marazza M et al. Fenretinide (4-HPR) in

chemoprevention of oral leukoplakia. J Cell Biochem 1993;

17F (Suppl.): 255–61.86 Sankaranarayanan R, Mathew B. Retinoids as cancer-

preventive agents. In: Stewart BW, McGregor D, Kleihues

P, eds. Principles of Chemoprevention. Lyon, France: IARC

Scientific Publishers, 1996; 47–60.87 Omenn GS. Micronutrients (vitamins and minerals) as

cancer-preventive agents. In: Stewart BW, McGregor D,

Kleihues P, eds. Principles of Chemoprevention. Lyon, France:

IARC Scientific Publishers, 1996; 33–46.88 Schwartz GG, Hulka BS. Is vitamin D deficiency a risk factor

for prostate cancer? (Hypothesis). Anticancer Res 1990; 10:

1307–11.89 Corder EH, Guess HA, Hulka BS et al. Vitamin D and prostate

cancer: a prediagnostic study with stored sera. Cancer

Epidemiol Biomarkers Prev 1993; 2: 467–72.

90 Giovannucci E. Dietary influences of 1,25(OH)2 vitamin D inrelation to prostate cancer: a hypothesis. Cancer Causes

Control 1998; 9: 567–82.

91 Christman JK, Sheikhnejad G, Dizik M, Abileah S, Wainfan E.

Reversibility of changes in nucleic acid methylation and geneexpression induced in rat liver by severe dietary methyl

deficiency. Carcinogenesis 1993; 14: 551–7.

92 Freudenheim JL, Graham S, Marshall JR, Haughey BP,

Cholewinski S, Wilkinson G. Folate intake and carcinogen-esis of the colon and rectum. Int J Epidemiol 1991; 20: 368–

74.

93 Giovannucci E, Stampfer MJ, Colditz GA et al. Folate, methi-onine, and alcohol intake and risk of colorectal adenoma.

J Natl Cancer Inst 1993; 85: 875–84.

94 Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide

incidence of eighteen major cancers in 1985. Int J Cancer1993; 54: 594–606.

95 Pisani P, Parkin DM, Ferlay J. Estimates of the worldwide

mortality from eighteen major cancers in 1985. Implications

for prevention and projections of future burden. Int J Cancer1993; 55: 891–903.

96 Lippman SM, Batsakis JG, Toth BB et al. Comparison of low-

dose isotretinoin with beta-carotene to prevent oral carcino-genesis. N Engl J Med 1993; 328: 15–20.

97 Cuzick J, Baum M. Tamoxifen and contralateral breast

cancer. Lancet 1985; 2: 282.

98 Cuzick J, Wang DY, Bulbrook RD. The prevention of breast

cancer. Lancet 1986; 1: 83–6.

99 Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for

prevention of breast cancer: report of the National SurgicalAdjuvant Breast and Bowel Project P-1 Study. J Natl Cancer

Inst 1998; 90: 1371–88.

100 Powles T, Eeles R, Ashley S et al. Interim analysis of the

incidence of breast cancer in the Royal Marsden Hospitaltamoxifen randomised chemoprevention trial. Lancet 1998;

352: 98–101.

101 Veronesi U, Maisonneuve P, Costa A et al. Prevention ofbreast cancer with tamoxifen: preliminary findings from the

Italian randomised trial among hysterectomised women.

Italian Tamoxifen Prevention Study. Lancet 1998; 352: 93–7.

102 Cuzick J. A brief review of the current breast cancerprevention trials and proposals for future trials. Eur J Cancer

2000; 36: 1298–302.

103 Cuzick J. Chemoprevention of breast cancer with tamoxifen.

In: Hakama M, Beral V, Buiatti E, Faivre J, Parkin DM, eds.Chemoprevention in Cancer Control. Lyon, France: IARC

Scientific Publisher, 1996; 95–109.

104 Cummings SR, Eckert S, Krueger KA et al. The effect ofraloxifene on risk of breast cancer in postmenopausal

women: results from the MORE randomized trial. JAMA

1999; 281: 2189–97.

105 Veronesi U, De Palo G, Marubini E et al. Randomized trial offenretinide to prevent second breast malignancy in women

with early breast cancer. J Natl Cancer Inst 1999; 91: 1847–56.

106 Tomatis L, ed. Cancer: Causes, Occurrence and Control. Lyon,

France: IARC Scientific Publisher, 1990.107 Nyren O. Is Helicobacter pylori really the cause of gastric

cancer? Semin Cancer Biol 1998; 8: 275–83.

108 Blot WJ, Li JY, Taylor PR et al. Nutrition intervention trials inLinxian, China: supplementation with specific vitamin/min-

eral combinations, cancer incidence and disease-specific

mortality in the general population. J Natl Cancer Inst

1993; 85: 1483–92.109 IARC. Overall Evaluations of Carcinogenicity: An Updating of

IARC Monographs. Vols 1–42. Lyon, France: IARC Scientific

Publishers, 1987.

110 IARC Hepatitis Viruses. IARC Monographs on the Evaluation ofCarcinogenic Risks to Humans, Vol. 59. Lyon, France: IARC

Scientific Publishers, 1994.

111 Kuper HE, Tzonou A, Kaklamani E et al. Hepatitis B and C

viruses in the etiology of hepatocellular carcinoma; a studyin Greece using third-generation assays. Cancer Causes

Control 2000; 11: 171–5.

112 Kuper H, Tzonou A, Kaklamani E et al. Tobacco smoking,alcohol consumption and their interaction in the causation of

hepatocellular carcinoma. Int J Cancer 2000; 85: 498–502.

113 Negri E, La Vecchia C, Franceschi S, D’Avanzo B, Parazzini F.

Vegetable and fruit consumption and cancer risk. Int J Cancer1991; 48: 350–4.

114 Kuper H, Tzonou A, Lagiou P et al. Diet and hepatocellular

carcinoma. Nutrition Cancer 2000c; 38: 6–12.

115 Kensler TW, He X, Otieno M et al. Oltipraz chemopreventiontrial in Qidong, People’s Republic of China: modulation of

serum aflatoxin albumin adduct biomarkers. Cancer Epidemiol

Biomarkers Prev 1998; 7: 127–34.116 Chuang SE, Kuo ML, Hsu CH et al. Curcumin-containing

diets inhibits diethylnitrosamine-induced murine hepato-

carcinogenesis. Carcinogenesis 2000; 21: 331–5.



117 Garidou A, Tzonou A, Lipworth L, Signorello LB, Kalapothaki

V, Trichopoulos D. Life-style factors and medical conditions

in relation to esophageal cancer by histologic type in a low-

risk population. Int J Cancer 1996; 68: 295–9.118 Tzonou A, Lipworth L, Garidou A, Signorello LB, Lagiou P.

Hsieh C-c, Trichopoulos D. Diet and risk of esophageal cancer

by histologic type in a low-risk population. Int J Cancer 1996;

68: 300–4.119 Li JY, Taylor PR, Li B et al. Nutrition intervention trials in

Linxian, China: multiple vitamin/mineral supplementation,

cancer incidence, and disease-specific mortality among adultswith esophageal dysplasia. J Natl Cancer Inst 1993; 85:

1492–8.

120 Wang GQ, Dawsey SM, Li JY et al. Effects of vitamin/mineral

supplementation on the prevalence of histological dysplasiaand early cancer of the esophagus and stomach: results from

the General Population Trial in Linxian, China. Cancer


121 Halpern MT, Gillespie BW, Warner KE. Patterns of absoluterisk of lung cancer mortality in former smokers. J Natl Cancer

Inst 1993; 85: 457–64.

122 Albanes D, Heinonen OP, Taylor PR et al. Alpha-Tocopheroland beta-carotene supplements and lung cancer incidence in

the alpha-tocopherol, beta-carotene cancer prevention study:

effects of base-line characteristics and study compliance.

J Natl Cancer Inst 1996; 88: 1560–70.123 Shouse TA, Day CL. Malignant melanoma. In: Weiss GR, ed.

Clinical Oncology. Norwalk, CT: Appleton & Lange, 1993;

247–56.

124 Parker SL, Tong T, Boldden S, Wingo PA. Cancer statistics,1997. CA Cancer J Clin 1997; 47: 5–27.

125 Marks R. An overview of skin cancers. Incidence and

causation. Cancer 1995; 75 (Suppl. 2): 607–12.126 Ananthaswamy HN, Pierceall WE. Molecular mechanisms of

ultraviolet radiation carcinogenesis. Photochem Photobiol

1990; 52: 1119–36.

127 Brash DE, Rudolph JA, Simon JA et al. A role for sunlight inskin cancer: UV-induced p53 mutations in squamous cell

carcinoma. Proc Natl Acad Sci USA 1991; 88: 10124–8.

128 Potten CS, Chadwick CA, Cohen AJ et al. DNA damage in UV-

irradiated human skin in vivo: automated direct measure-ment by image analysis (thymine dimers) compared with

indirect measurement (unscheduled DNA synthesis) and

protection by 5-methoxypsoralen. Int J Radiat Biol 1993; 63:

313–24.129 Yang CS, Wang ZY. Tea and cancer. J Natl Cancer Inst 1993;

85: 1038–49.

130 Okuda T, Mori K, Hayatsu H. Inhibitory effect of tannins ondirect-acting mutagens. Chem Pharm Bull 1984; 32: 3755–8.

131 Mukhtar H, Katiyar SK, Agarwal R. Green tea and skin

anticarcinogenic effects. J Invest Dermatol 1994; 102: 3–7.

132 Gensler HL, Timmermann BN, Valcic S, Wachter GA, Dorr Ret al. Prevention of photocarcinogenesis by topical adminis-

tration of pure epigallocatechin gallate isolated from green

tea. Nutr Cancer 1996; 26: 325–35.

133 Moon TE, Levine N, Cartmel B et al. Effect of retinol inpreventing squamous cell skin cancer in moderate-risk

subjects: a randomized, double-blind, controlled trial. South-

west Skin Cancer Prevention Study Group. Cancer EpidemiolBiomarkers Prev 1997; 6: 949–56.

134 Axelrod M, Serafin D, Klitzman B. Ultraviolet light and free

radicals: an immunologic theory of epidermal carcinogenesis.

Plast Reconstr Surg 1990; 86: 582–93.

135 Kwa R, Campana K, Moy RL. Biology of cutaneous squamouscell carcinoma. J Am Acad Dermatol 1992; 26: 1–26.

136 Shimizu H, Ross RK, Bernstein L, Yatani R, Henderson BE,

Mack TM. Cancers of the prostate and breast among Japanese

and white immigrants in Los Angeles County. Br J Cancer1991; 63: 963–6.

137 Willett WC, Trichopoulos D. Nutrition and cancer: a summary

of the evidence. Cancer Causes Control 1996; 7: 178–80.138 Tsukamoto S, Akaza H, Imada S et al. Chemoprevention of

rat prostate carcinogenesis by use of finasteride or casodex.

J Natl Cancer Inst 1995; 87: 842–3.

139 Zaccheo T, Giudici D, di Salle E. Effect of early treatment ofprostate cancer with the 5-alpha-reductase inhibitor turo-

steride in Dunning R3327 prostatic carcinoma in rats.

Prostate 1998; 35: 237–42.

140 Stoner E. Three-year safety and efficacy data on the use offinasteride in the treatment of benign prostatic hyperplasia.

Urology 1994; 43: 284–92.

141 Heinonen OP, Albanes D, Virtamo J et al. Prostate cancer andsupplementation with alpha-tocopherol and beta-carotene:

incidence and mortality in a controlled trial. J Natl Cancer Inst

1998; 90: 440–6.

142 Clark LC, Dalkin B, Krongrad A et al. Decreased incidence ofprostate cancer with selenium supplementation: results of a

double-blind cancer prevention trial. Br J Urol 1998; 81:

730–4.

143 Hoque A, Albanes D, Lippman SM et al. Molecular epidem-iologic studies within the Selenium and Vitamin E Cancer

Prevention Trial (SELECT). Cancer Causes Control 2001; 12:

627–33.144 de Vos S, Holden S, Heber D et al. Effects of potent vitamin D3

analogs on clonal proliferation of human prostate cancer cell

lines. Prostate 1997; 31: 77–83.

145 Berrino F, Esteve J, Coleman MP (eds) Survival of CancerPatients in Europe: The EUROCARE Study. Lyon, France: IARC

Scientific Publishers, 1995.

146 Vogelstein B, Fearon ER, Hamilton SR et al. Genetic altera-

tions during colorectal-tumor development. N Engl J Med1988; 319: 525–32.

147 Benito E, Stiggelbout A, Bosch FX et al. Nutritional factors in

colorectal cancer risk: a case control study in Majorca. Int J

Cancer 1991; 49: 161–7.148 Ferraroni M, La Vecchia C, D’Avanzo B, Negri E, Franceschi

S, Decarli A. Selected micronutrient intake and the risk of

colorectal cancer. Br J Cancer 1994; 70: 1150–5.149 Baron JA, Sandler RS, Haile RW, Mandel JS, Mott LA,

Greenberg ER. Folate intake, alcohol consumption, cigarette

smoking, and risk of colorectal adenomas. J Natl Cancer Inst

1998; 90: 57–62.150 Giovannucci E, Stampfer MJ, Colditz GA et al. Multivitamin

use, folate, and colon cancer in women in the Nurse’s’ Health

Study. Ann Intern Med 1998; 129: 517–24.

151 Nagengast FM, Grubben MJAL, van Menster IP. Role of bileacids in colorectal carcinogenesis. Eur J Cancer 1995; 31A:

1067–70.

152 Pence BC. Role of calcium in colon cancer prevention: experi-mental and clinical studies. Mutat Res 1993; 290: 87–95.



153 Hyman J, Baron JA, Dain BJ et al. Dietary and supplemental

calcium and the recurrence of colorectal adenomas. Cancer


154 Martinez ME, Willett WC. Calcium, vitamin D and colorectalcancer: a review of the epidemiologic evidence. Cancer


155 Baron JA, Beach M, Mandel JS et al. Calcium supplements for

the prevention of colorectal adenomas. N Engl J Med 1999;340: 101–7.

156 Boolbol SK, Dannenberg AJ, Chadburn A et al. Cyclooxygen-

ase-2 overexpression and tumor formation are blocked bysulindac in a murine model of familial adenomatous

polyposis. Cancer Res 1996; 56: 2556–60.

157 Piazza GA, Alberts DS, Hixson LJ et al. Sulindac sulfone

inhibits azoxymethane-induced colon carcinogenesis in ratswithout reducing prostaglandin levels. Cancer Res 1997; 57:

2909–15.

158 Dubois RN. Review article: cyclooxygenase – a target for

colon cancer prevention. Aliment Pharmacol Ther 2000; 14(Suppl. 1): 64–7.

159 Reddy BS, Rao CV. Colon cancer: a role for cyclo-oxygenase-

2-specific nonsteroidal anti-inflammatory drugs. Drugs Aging2000; 16: 329–34.

160 Gann PH, Manson JE, Glynn RJ, Buring JE, Hennekens CH.

Low-dose aspirin and incidence of colorectal tumors in a

randomized trial. J Natl Cancer Inst 1993; 85: 1220–4.161 Ma J, Pollak MN, Giovannucci E et al. Prospective study of

colorectal cancer risk in men and plasma levels of insulin-like

growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer

Inst 1999; 91: 620–5.

162 Calle EE, Miracle-McMahill HL, Thun MJ, Heath CW Jr.

Oestrogen replacement therapy and risk of fatal colon cancer

in a prospective cohort of postmenopausal women. J Natl

Cancer Inst 1995; 87: 517–23.163 Grodstein F, Martinez ME, Platz EA et al. Postmenopausal

hormone use and risk for colorectal cancer and adenoma.

Ann Intern Med 1998; 128: 705–12.

164 Kampman E, Potter JD, Slattery ML, Caan BJ, Edwards S.Hormone replacement therapy, reproductive history, and

colon cancer: a multicenter, case-control study in the United

States. Cancer Causes Control 1997; 8: 146–58.165 Fernandez E, La Vecchia C, Braga C et al. Hormone replace-

ment therapy and risk of colon and rectal cancer. Cancer


166 Alberts DS, Martinez ME, Roe DJ et al. Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal

adenomas. N Engl J Med 2000; 342: 1156–62.

167 Schatzkin A, Lanza E, Corle D et al. Lack of effect of a low-fat,

high-fiber diet on the recurrence of colorectal adenomas.Polyp Prevention Trial Study Group. N Engl J Med 2000;

342: 1149–55.

Received 20 September 2001; revision received 12 November

2001; accepted 24 January 2002.

Correspondence: Rulla M. Tamimi, MS, Epidemiology Depart-

ment, Harvard School of Public Health, 677 Huntington Ave.,Boston, MA 02115, USA (fax: +1 617 566 7805,

e-mail: [email protected]).



ta mimi 2002

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