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Inhibition of Carcinogenesis by Minor Dietary Constituents
Lee W. Wattenberg
Cancer Res 1992;52:2085s-2091s. Published online April 1, 1992.
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Copyright © 1992 American Association for Cancer Research
(CANCER RESEARCH (SUPPL.) 52. 2085s-2091s. April I. 1992)
Inhibition of Carcinogenesis by Minor Dietary Constituents1
Lee W. Wattenberg2
Laboratory of Medicine and Pathology, I'niversity of Minnesota, Minneapolis, Minnesota 55455
Abstract
A major foundation of the field of cancer chemoprevention has resided
in an impressive number of animal studies showing that cancer can be
prevented by a variety of chemical compounds. In the search for increas
ingly effective inhibitors, both synthetic and naturally occurring com
pounds are being investigated. One group of naturally occurring com
pounds of particular interest consists of minor dietary nonnutrients. Foods
of plant origin frequently contain as much as several per cent of these
compounds. In recent years there has been a growing awareness that they
may have important effects on the consequences of exposure to carcino
genic agents. This information comes from studies of whole diets; indi
vidual dietary constituents, particularly those from plants; and finally
from investigations of pure compounds. The nonnutrient inhibitors of
carcinogenesis have several different mechanisms of action. Some are
blocking agents; i.e.. they prevent carcinogens from reaching or reacting
with critical target sites. Others are suppressing agents; i.e., they prevent
evolution of the neoplastic process in cells that otherwise would become
malignant. Occasionally, one compound will show both mechanisms. The
nonnutrient compounds have the important attribute of there being data
on their consumption by humans. Thus, it may be possible to evaluate
their impact on cancer risk. Ultimately, information pertaining to these
compounds may be useful in terms of diet selection or their use as dietary
supplements.
Cancer can be prevented by a surprisingly large number of
chemical compounds. This type of prevention is referred to as
chemoprevention. Two forms exist: one, general population
chemoprevention, entails efforts at providing measures appli
cable to large population groups; the other, targeted chemopre
vention, is directed toward individuals at increased risk of
cancer in specific tissues. The two differ in terms of allowable
toxicity and specificity of agent targeting. Driving forces for
general population chemoprevention have been both epidemiological and experimental data indicating protective effects of
dietary constituents against the occurrence of cancer. Epidemiological studies have shown that diets containing large quan
tities of vegetables and, to a lesser extent, fruits are associated
with relatively low risks of cancer. The assignment of which
constituents of these foods of plant origin are responsible for
protection has been indecisive. In the search for inhibitory
compounds, a group currently under investigation is that of the
minor nonnutrient constituents of the diet. This presentation
provides an overview of experimental studies in which members
of this very diverse group of compounds have been shown to
inhibit carcinogenesis. The implications of these data could be
quite profound. Ultimately, they could be relevant to decisions
on food selection and composition for the purpose of providing
increased protection against cancer as well as for possible use
of individual compounds as specific dietary adjuncts.
Foods contain major and minor constituents. The major ones
are protein, fat, carbohydrate, and fiber. The minor ones are
nutrients such as vitamins and minerals and a large number of
nonnutrients, i.e., compounds with no known nutritional value.
Nonnutrient compounds will be the principle focus of this
' Presented at "Nutrition and Cancer," the first conference of the International
Conference Series on Nutrition and Health Promotion, April 17-19, 1991,
Atlanta, GA. The research described was supported by Grant SIG 5 from The
American Cancer Society.
2To whom requests for reprints should be addressed.
paper; many are unfamiliar to individuals in the biomédical
sciences, including specialists in nutrition. They have been
ignored because they seem to be biologically quite inert. How
ever, it is becoming apparent that some of these compounds
can have rather profound effects in cancer prevention.
The role of nonnutrients in the diet in preventing cancer
comes from three levels of data, each of which is successively
more defined. The first level consists of data derived from
studies in which comparisons of carcinogenic responses were
made between animals fed crude diets composed of natural
constituents containing both nutrients and nonnutrients and
semipurified diets composed mainly of purified materials and
almost completely lacking nonnutrients. Several of these exper
iments show a lower tumor response in animals fed the crude
diets (1-4). The results are important because they suggest a
protective role of nonnutrients in some carcinogenic processes
and because the concentration of the nonnutrients in conven
tional diets is adequate to bring about this preventive effect.
The second level of information comes from studies of single
components, such as vegetables, fruits, or crude products de
rived from plant sources. In several instances, inhibition of
carcinogenesis was found. Finally, experiments with a large
number of specific dietary nonnutrient compounds, particularly
from vegetables and fruits, show protection against neoplasia.
Comparisons between the Effects of Crude and Semipurified
Diets on the Carcinogenic Response of Experimental Animals
Studies from the early work of Silverstone et al. (Ì)
demon
strated that in some experiments animals fed a crude diet were
at lesser risk of developing cancer than were those fed a semipurified diet. The crude diets (Purina chow) contain compo
nents such as grain, beet pulp, alfalfa meal, cane molasses, fish
meal, and other crude materials. In contrast, semipurified diets
consist of defined dietary constituents, such as casein, starch,
corn oil, minerals, and vitamins. The term semipurified means
that some of these constituents, principally vegetable oils, are
not pure. The two types of diets are nutritionally comparable
but differ profoundly in amounts of nonnutrients. In one inves
tigation, male DBA or C3H mice placed on the two different
types of diets developed hepatomas spontaneously. In a series
of experiments, 2 to 5 times as many of the mice fed the
semipurified diet developed hepatomas compared with groups
fed the crude diet. In some experiments of cancers of other sites
such as skin cancers, mammary cancers, and leukemias, the
results were indecisive or no effects were found.
More recently, the effects of feeding AIN-76, a semipurified
diet, and NIH-07, a crude diet, were compared for carcinogeninduced neoplasia in mice given the tobacco-specific carcinogen,
NNK-' (2). Feeding of the diets was begun 2 weeks before
carcinogen challenge and continued for the duration of the
protocol. The animals fed the semipurified diet had 3 times as
many pulmonary adenomas as did those fed the crude diet.
'The abbreviations used are: NNK, 4-(methylnitrosatnino)-l,3-(pyridyl)-lbutanone; BP, benzo(a)pyrene; DMBA, 7,12-dimethylbenz(a)anthracene; AMT,
ally! methyl trisulfide; AMD, allyl methyl disulfide; DAT. diallyl trisulfide; DAS,
diallyl sulfide.
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NONNUTRIENT
INHIBITORS OF CARCINOGENESIS
These data agree with epidemiological investigations in which
a protection by vegetables against lung cancer in the humans
was observed (5).
In other experiments, the comparisons focused on either the
initiation or postinitiation phases of carcinogenesis. One study
compared a crude diet (Purina rat chow) with a semipurified
diet (Teklad) in mice during the initiation phase. Two experi
ments were performed, one with /3-propiolactone and one with
BP (3). Animals were placed on the experimental diets 2 weeks
before carcinogen challenge and were maintained on the diets
until 1 day after the last dose of carcinogen. The target organ
was the forestomach. In the first experiment, mice treated with
/3-propiolactone and fed the crude diet had approximately onethird as many forestomach tumors as did those fed the semipurified diet. In the second experiment, with BP-induced neo
plasia, no difference in carcinogenic response was observed.
This experiment shows that the dietary effects on initiation by
different carcinogens can vary.
A study aimed at investigating the effects of feeding a crude
with a semipurified diet on the postinitiation phase of carcino
genesis was carried out by Longnecker et al. (4, 6). The exper
imental model was azaserine-induced neoplasia of the pancreas
in rats. These investigators showed that feeding a crude diet
during the postinitiation phase resulted in a lower incidence of
pancreatic neoplasia compared with feeding a semipurified diet.
In summary, a number of experiments show that the carcino
genic response of animals fed crude diets was less than in those
fed a semipurified diet. The crude diets contain an abundance
of nonnutrient dietary constituents whereas the semipurified
diets contain relatively small quantities. Thus, these studies
provide an initial indication that nonnutrient dietary constitu
ents are inhibitors of carcinogenesis.
Effects of Single Crude Dietary Constituents on Carcinogeninduced Neoplasia in Experimental Animals
Single crude dietary constituents have been added to semipurified diets so that their effects on the carcinogenic response
could be studied. The results of adding cruciferous vegetables
were studied with DMBA-induced neoplasia in Sprague-Dawley
rats. In this experimental model, the animals develop mammary
tumors after a single administration of DMBA by p.o. intuba
tion. Frozen-thawed pieces of vegetable were placed in the cages
once a day (7). The animals consume this type of vegetable
supplement very rapidly thereby mimicking human meal con
sumption. The vegetable supplements were provided beginning
1 week after carcinogen administration only during the postin
itiation phase of carcinogenesis. Under these conditions, cab
bage and broccoli inhibited mammary tumor formation. In
another study with this tumor model, orange oil was added to
a semipurified diet. A dose-dependent inhibition of mammary
tumor formation resulted (8). In other experiments, the effects
of onion and garlic oils on epidermal carcinogenesis in mouse
were studied. Topical applications of these two oils produced
inhibition in the postinitiation phase in this animal model (9).
In other work, extracts of plant materials containing protease
inhibitors inhibited the postinitiation phase of carcinogenesis
of the skin, breast, large bowel, and lung (10). Green tea
administered in the drinking water was recently shown to inhibit
carcinogenesis in mice (II).4
' A. Conney, unpublished observations.
Inhibition of Carcinogenesis by Specific Nonnutrient
Constituents of the Diet
The finding of specific compounds of plant origin with inhib
itory effects on carcinogenesis has resulted from two lines of
investigation. One of these is the identification of a constituent
in crude plant materials. The plant material used had carcino
gen-inhibitory effects or produced a biological response, such
as enhancement of detoxification systems, likely to result in
cancer prevention. In these studies, o-limonene, a major con
stituent of citrus fruit oils that inhibits carcinogenesis, was
found to be preventive (12). Several groups of inhibitors also
were identified in cruciferous vegetables. These include Ã-ndoles,
aromatic isothiocyanates, dithiolethiones, and phenols. Studies
to identify the active constituents of garlic and onion oils that
inhibit carcinogenesis showed a number of organosulfur com
pounds in these oils that have inhibitory properties (13, 14).
The second type of investigation that identified nonnutrient
dietary inhibitors focused initially on synthetic compounds.
Subsequently, these structurally related compounds were found
in natural products. Initial studies of synthetic chemicals re
sulted in identification of flavone as an inhibitor. Flavone, itself,
is a synthetic compound. However, a large number of naturally
occurring flavone derivatives were found to inhibit carcinogen
esis (15-17).
The mechanisms of action of many of the minor nonnutrient
inhibitors of carcinogenesis are poorly understood, making it
difficult to organize them into a precise pattern. One organi
zational framework is classification of inhibitors by the time in
carcinogenesis when they are effective. In this framework, in
hibitors can be divided into three categories. The first consists
of compounds that prevent the formation of carcinogens from
precursor substances. The second contains compounds that
inhibit carcinogenesis by preventing carcinogenic agents from
reaching or reacting with critical target sites in the tissues.
These inhibitors are called blocking agents, which describes
their mechanism of action (they exert a barrier function). Inhib
itors of the third category act subsequent to exposures to
carcinogenic agents. These are termed suppressing agents be
cause they act by suppressing the expression of neoplasia in
cells previously exposed to doses of carcinogens that otherwise
would cause cancer (15). Studies of various inhibitors have
made it apparent that some inhibitors act at more than one
time in the carcinogenic process (7).
Blocking Agents
Blocking agents prevent carcinogens from reaching or react
ing with critical target sites by several mechanisms. One mech
anism is inhibiting of reactions requiring metabolic activation.
A second entails inducing of activities of enzyme systems that
detoxify carcinogens. A third is the trapping of reactive carcin
ogenic species. Some blocking agents prevent the action of
tumor promoters by preventing the promoter from reaching or
reacting with its cellular target or by blocking subsequent cell
ular events required for tumor promotion to occur. A list of
nonnutrient blocking agents is shown in Table 1.
Blocking Agents That Act by Inhibiting Carcinogen Activation.
Several groups of nonnutrient compounds prevent carcinogen
esis by inhibiting carcinogen activation reactions (Table 2).
Almost all carcinogens occurring in food require metabolic
activation. Examples of such carcinogens are include aflatoxin,
nitrosamines, polycyclic aromatic hydrocarbons, hydrazines,
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NONNUTRIENT
INHIBITORS OF CARCINOGENESIS
Table 1 Some nonnutrient blocking agents in food
Ellagic acid (29-31)
Curcumin (25, 32)
Coumarins (15)
Conjugated dienoic linoleic acids (25, 33)
Nucleophiles(15, 25)
tÃ--Carotene(25)
18-/3-Glycyrrhetinic acid (34)
Glucarates (35-37)
Terpenes(12. 15, 18)
Organosuindes(14. 18-21)
Aromatic isothiocyanates
(15, 22, 23)
Ã-ndoles(13, 15)
Dithiolethiones (24, 25)
Phenols (15)
Flavones(15-17, 26)
Tannins (11, 27,28)
and heterocyclic amines. Thus, blocking agents inhibiting acti
vation of these and other carcinogens may play a role in
preventing neoplasia resulting from this type of exposure. Ben
zyl isothiocyanate is one such naturally occurring blocking
agent. Benzyl isothiocyanate, found in cruciferous vegetables,
is formed by the hydrolysis of the glucosinolate glucotropaeolin.
The glucosinolate is the storage form in plant material. When
plants are processed or damaged, the glucosinolate undergoes
hydrolysis with resultant formation of the free aromatic iso
thiocyanate (39). Early experiments showed that benzyl isothio
cyanate inhibited DMBA-induced mammary tumor formation
in rats when given by p.o. intubation 2 h before the carcinogen
(38). More recently, the effects of benzyl isothiocyanate on
nitrosamine metabolism in rat liver microsomes and cultured
esophagus were studied by Chung et al. (40, 41). These inves
tigators found that administration of benzyl isothiocyanate 2 h
before killing markedly inhibited activation of yV-nitrosodimethylamine and the tobacco-specific carcinogen, NNK. Subse
quently, benzyl isothiocyanate administered by gavage 15 min
before p.o. carcinogen challenge inhibited the neoplastic effects
of JV-nitrosodiethylamine and BP (22, 38).
Organosulfur compounds found in Allium species, including
garlic, onions, leeks, and shallots (42-44) are a second group
of naturally occurring compounds that can inhibit carcinogenesis by preventing carcinogen activation. In one series of exper
iments, they inhibited 7V-nitrosodiethylamine-induced
carcinogenesis of the forestomach and, to a lesser extent, the lungs
in female A/J mice (18). The most potent of the naturally
occurring organosulfur compounds was diallyl disulfide. In
other studies Wargovich et al. (19) showed that diallyl sulfide
inhibits yV-nitrosomethylbenzylamine-induced
esophageal can
cer in rats when the organosulfur compound was administered
p.o. 3 h before nitrosamine. In related work, Brady et al. (45)
demonstrated that diallyl sulfide inhibits microsomal metabo
lism of nitrosamines by rats when administered 3 h before the
rats are killed. Inhibition of 1,2-dimethylhydrazine-induced
neoplasia of the large bowel in mice by diallyl sulfide was also
observed when this compound was administered p.o. 3 h before
the carcinogen (14).
A third group of naturally occurring compounds that inhibit
carcinogen activation and carcinogenesis when given shortly
before carcinogen exposure are monoterpenes. Two such com
pounds have been investigated, D-limonene and o-carvone. DLimonene is a major constituent of citrus fruit oils (46). For
example, orange oil contains more than 90% D-limonene. DCarvone is a major constituent of caraway seed oil. This oil
contains approximately 50% o-carvone (47). o-Limonene, Dcarvone, orange oil, and caraway seed oil all have been found
to inhibit activation of dimethylnitrosamine.5 Carcinogenesis
experiments have been performed in which D-limonene, Dcarvone, or caraway seed oil were administered p.o. to female
A/J mice l h before NDEA (18). All three substances pro5 L. W. Wattenberg and J. L. Leong, unpublished observations.
foundly inhibited forestomach tumor formation and the occur
rence of pulmonary adenomas in these animals. More recently,
D-limonene and citrus fruit oils were found to inhibit the
carcinogenicity of NNK (48).
Glucobrassicin and glucotropaeolin, two glucosinolates oc
curring in cruciferous vegetables, were also found to inhibit
DMBA-induced mammary neoplasia in rats when administered
by gavage 4 h before the carcinogen. Thus, data now show that
four widely occurring groups of naturally occurring compounds,
i.e., aromatic isothiocyanates, organosulfur compounds found
in Allium species, monoterpenes, and glucosinolates, can inhibit
carcinogenesis if administered shortly before carcinogen chal
lenge (Table 2).
Blocking Agents That Act by Increasing Carcinogen Detoxifi
cation. Blocking agents can prevent the occurrence of neoplasia
by increasing the detoxification of carcinogens. Two general
categories of blocking agents acting by this mechanism have
been identified. They are designated type A and type B inhibi
tors (15). Type A inhibitors induce an increase in activity of
phase 2 enzymes, which perform conjugation and other reac
tions that detoxify many carcinogenic agents. Prominent among
these is the marked increase in glutathione 5-transferase activ
ity. UDP-glucuronosyltransferase,
epoxide hydrolase, and
NAD(P)H-quinone reducÃ-aseactivities are also enhanced. In
creases in tissue glutathione levels are found. Type B inhibitors
enhance both phase I and phase 2 enzyme activities. The phase
1 enzymes include the cytochrome P-450 systems and are very
complex. Reviews of the effects of type A and type B inhibitors
have been published (15).
Because type A inhibitors are effective, there have been a
continuing effort to identify compounds in this category of
chemopreventive agents. Recent work has focused on the or
ganosulfur compounds found in Allium species. In initial stud
ies, the capacity of AMT to induce increased glutathione 5transferase activity in rodent tissues was investigated. AMT
induces increased activity of this enzyme system when given 4
and 2 days before assay. With this administration schedule,
AMT was also found to inhibit BP-induced neoplasia of the
forestomach of female A/J mice (20). Experimental protocols
with the test compound being given 4 and 2 days before carcin
ogen challenge are commonly used in studying the inhibitory
effects of agents that act by inducing increased activity of
detoxification systems.
Other organosulfur compounds were studied under these
same conditions. Ultimately, the experiments have included
four allyl group-containing compounds with one, two, or three
linearly connected sulfur atoms: AMT, AMD, DAT, and DAS.
Four corresponding saturated compounds in which propyl
groups are substituted for the allyl groups also were studied.
All four allylic compounds inhibited BP-induced neoplasia of
the forestomach. Their saturated analogues showed almost no
inhibitory activity, indicating the importance of allyl groups.
DAT, with two allyl groups, was more potent than AMT, with
one, providing evidence for the role of allyl groups in the
inhibitory effects observed. DAS and AMD, but not DAT or
AMT, inhibited pulmonary adenoma formation (20). The fact
that monosulfide and disulfide inhibit tumor formation in the
lung but that trisulfide does not indicates that the number of
sulfur atoms in the molecule can control the organ sites at
which protection against carcinogenesis occurs. All four allylic
compounds induce increased glutathione 5-transferase activity
in the forestomach but vary in capacity to induce glutathione
5-transferase activity in the lung, liver, and small bowel. Their
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NONNUTRIENT INHIBITORS OF CARCINOGENESIS
Table 2 Blocking agents preventing neoplasia by inhibiting carcinogen activation
GroupAromatic
isothiocyanatesOrganosulfur
isothiocyanate
isothiocyanateDiallyl
Phenethyl
compoundsMonoterpenesGlucosinolatesCompoundsBenzyl
suinde
Diallyl disulfide
AIM mercaptan
Allyl
disulfiden-Limonene
methyl
r>-CarvoneGlucobrassicin
vegetables
vegetablesAllium
Cruciferous
inhibitedNDEA,"
BP, DMBA
NDEA. BP. DMBA,
NNKDMH,
sp.
Allium sp.
Allium sp.
Allium
sp.Citrus
NMBA
NDEA
NDEA
NDEANDEA,
fruit oils
oilCruciferous
Caraway
seed
NNK
NDEADMBA
19
18
18
18«.*1313
vegetables
GlucotropaeolinSourceCruciferous Cruciferous vegetablesCarcinogensDMBARef.22,3822,2314,
" NDEA, jV-nitrosodiethylamine; DMH, 1,2-dimethylhydrazine; NMBA, W-nitrosomethylbenzylamine.
* L. W. Wattenberg and J. Coccia, unpublished.
saturated analogues produced little or no induction (20). Like
the organosulfur compounds from Allium species, aromatic
isothiocyanates from cruciferous vegetables, in particular, ben
zyl isothiocyanate, induce increased glutathione S-transferase
activity and have other properties of type A inhibitors.
Blocking Agents Effective against Tumor Promoters. A num
ber of naturally occurring nonnutrient inhibitors of tumor pro
motion have been found. A property for identifying inhibitors
of this type is their capacity to prevent an increased ornithine
decarboxylase activity after exposure to the promoter. This
assay has been particularly effective in mouse epidermis. How
ever, in other instances, biological responses such as inhibition
of increased cellular proliferation or tumor formation in re
sponse to promoter administration has been the means by which
the inhibitor was identified. Table 1 lists compounds that inhibit
tumor promotion, including phenols, flavones, tannins, curcumin, glycyrrhetinic acid, and glucarates. Mechanisms by which
these inhibitors work include inhibition of components of the
arachidonic acid cascade, antioxidant activity, and modulation
of hormonal responses.
Suppressing
Agents
Suppressing agents prevent the evolution of the neoplastic
process in cells previously exposed to doses of carcinogenic
agents that otherwise would cause cancer (15). Table 3 lists
minor nonnutrient constituents of the diet that can act as
suppressing agents in animal models. The number of suppress
ing agents identified is considerably smaller than the number
of blocking agents. The mechanisms by which blocking agents
act are relatively simple, although the systems themselves can
be very complex. The mechanism of action for suppressing
agents is not well defined, as might be expected because the
events that they counteract are those basic to cancer, also a
poorly understood process. Suppressing agents act during the
earliest stages of the neoplastic process, when the number of
pathological alterations is considerably smaller than at later
stages (55). As more information becomes available concerning
the multiple events leading to malignancy, targeting of sup
pressing agents to counteract defined early changes may be
Table 3 Some nonnutrient suppressing agents in food
Protease inhibitors (10)
Inhibitors of the arachidonic acid cascade (49-51)
Terpenes(12)
Aromatic isothiocyanates (IS)
Inositol hexaphosphate (52, 53)
Nerolidol (57)
feasible. The vast amount of data indicates that alterations in
genetic material occur during carcinogenesis. Correcting ge
netic alterations during neoplastic changes in solid tissues is
difficult. Suppressing agents can modulate consequences of the
genetic changes but are not likely to correct the genetic defects
themselves. Accordingly, it would be anticipated that suppress
ing agents may have reversible effects. Consequently, it is likely
that continuous administration of suppressing agents will be
necessary to sustain inhibition of carcinogenesis. Retinoids, the
most extensively investigated of the suppressing agents, dem
onstrate this characteristic both in vitro and in vivo. Suppression
is maintained as long as the agent is present; on removal, the
neoplastic process recurs.
Studies of crude diets for suppressing effects are relatively
sparse. One such study cited previously was carried out by
Longnecker et al. (4, 6), who demonstrated a suppressing effect
of crude diets on the occurrence of pancreatic cancer. This study
is not definitive, because animals fed the crude diet gained less
weight than did those fed the semipurified diet. It is well
established that retarding weight gain also can diminish the
carcinogenic response. However, the difference in the incidence
of pancreatic neoplasms between the two groups of animals was
greater than expected from the modest difference in weight
gain.
Suppressing agents have been found in individual dietary
constituents. Studies with cruciferous vegetables and with or
ange oil demonstrated suppressing effects (8). In the initial
studies with cruciferous vegetables, dehydrated powders pre
pared from Chieftain Savoy cabbage inhibited DMBA-induced
mammary-tumor formation. In further investigations, it was
found that frozen-thawed segments of cabbage leaf placed di
rectly in cages produced a comparable reduction of neoplasia
in the animals (56). The amount of cabbage leaf fed was of the
order of 5 g/kg body weight/day. More recently, similar studies
with frozen-thawed segments of broccoli and cabbage were
given beginning 1 week after DMBA and continued for 18
weeks after DMBA. The rats were fed a semipurified diet, and
the vegetable additions were given 6 days a week. The results
showed that fewer animals receiving cabbage had mammary
tumors compared with nonsupplemented controls (100% versus
56%) and that the average number of tumors per rat was
diminished markedly (2.5 versus 0.8). Similar findings were
obtained with broccoli (56).
Possibly related to the suppressive effects of cruciferous
vegetables is the finding that benzyl isothiocyanate, a constitu
ent of these plants, will inhibit DMBA-induced mammary
carcinogenesis when administered beginning 1 week after
DMBA challenge (15, 38). Suppressive effects also were pro-
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NONNt'TRIENT
INHIBITORS OF CARC1NOGENF.SIS
duced by orange oil or its principal constituent, D-limonene (8,
12). In recent studies, nerolidol, a sesquiterpene structurally
related to farnesol, suppressed azoxymethane-induced neopla
sia of the large bowel in rats (57). The observation that sup
pressing agents occur in commonly consumed foods indicates
that further searches should be made for this category of chemopreventive agents.
Table 3 lists some defined minor nonnutrient dietary constit
uents that have suppressing activity. Included are protease
inhibitors, a very interesting group of suppressing agents. The
in vitro data showing their suppressive effect are striking. Some
in vivo studies have also shown inhibition, but not many of such
investigations have been performed (10). Another group of
suppressing agents with a common characteristic are inhibitors
of components of the arachidonic acid cascade. This group
includes various polyphenolic compounds. Studies with syn
thetic inhibitors of the arachidonic acid cascade, such as indomethacin and piroxicam, demonstrated a suppressive effect,
thus suggesting that the naturally occurring compounds may
act similarly (49-51). Inhibitors of the arachidonic acid cascade
can be potent inhibitors of tumor promotion (5). The relation
ship between their mechanisms of suppression and inhibition
of tumor promotion is not clear. Two additional groups of
naturally occurring suppressing agents are the terpenes and
isothiocyanates (12, 15). Further work is required to more fully
evaluate their potential role as suppressing agents.
Most of the research with suppressing agents has focused on
synthetic compounds and a few minor dietary compounds that
are nutrients. As mentioned previously, the retinoids, synthetic
analogues of vitamin A, are the most extensively studied sup
pressing agents. Vitamin A has only limited suppressing activity
(54). It is relatively toxic at the large amounts generally used
for suppression. However, in a careful study by Zile et al. (58),
moderate supplementation of the diet with vitamin A inhibited
carcinogen-induced mammary neoplasia in rats. ß-Carotenehas
also been studied extensively for its suppressing activity in
animal systems. Many of these studies have given negative
results. A few studies giving positive results were published
(59). Selenium salts and inositol hexaphosphate were also
shown to have suppressing effects (60-63).
Inhibitors with Both Blocking and Suppressing Activity
During studies of inhibitors of carcinogenesis, some sub
stances showed both blocking and suppressing effects. The first
was sodium cyanate, where both blocking and suppressing
effects against DMBA-induced mammary carcinogenesis in rats
( 15). Subsequently, cruciferous vegetables were shown to have
these characteristics, as was one of their constituents, benzyl
isothiocyanate. In experiments with cabbage, consumption of a
semipurified diet with added dehydrated powders prepared from
Chieftain Savoy cabbages showed blocking effects against
DMBA-induced mammary carcinogenesis in rats. It was also
found that consumption of the cabbage powders beginning 1
week after DMBA administration suppressed mammary tumor
formation. Subsequently, benzyl isothiocyanate was shown to
block DMBA-induced mammary carcinogenesis and to sup
press formation of mammary tumors under similar conditions
to those used with crude plant materials (15).
Citrus fruit oils were also found to have both blocking and
suppressing capacities. The most extensively studied is orange
oil, which has a blocking effect against DMBA-induced mam
mary neoplasia and a suppressive effect in this experimental
model (8). o-Limonene, found in orange oil, was shown to have
both blocking and suppressing effects against DMBA-induced
mammary tumor formation (12). Inhibitors having both block
ing and suppressing capacities, such as cruciferous vegetable
powders, benzyl isothiocyanate, orange oil, and D-limonene,
have another property in common; They all induce increased
glutathione 5-transferase activity in mouse tissues. The signif
icance of this relationship remains to be explained.
The finding of inhibitors with both blocking and suppressing
activity appears important. However, mechanisms for these
dual inhibitory actions are not known. Two distinctive possi
bilities merit consideration. One is that a coordinated protective
system against potentially toxic compounds exists that includes
both a detoxification component and a suppressive component.
The latter would be a fail-safe means of protection should the
former be not completely effective. On exposure to toxic com
pounds, the detoxification system constitutes the first line of
defense. Phase 2 enzymes, as well as glutathione, are compo
nents of this detoxification (blocking) defense. Because blocking
effects may not always be completely successful, a second line
of defense might prevent manifestations of damage that occurs,
i.e., suppression.
Whereas a coordinated protective mechanism entailing in
creased activity of detoxification systems and suppression of
manifestations of toxicity appears to be a reasonable possibility,
the inclusion of a decrease in cytochrome P-450 enzyme activ
ities might appear incongruous. However, an insight into how
such enzyme inhibitions might fit into an overall protective
system was provided by experiments that show that some
compounds that reduce cytochrome P-450 activity increase
interferon levels in tissues (64, 65). Such findings suggest that
a decrease in activity of one mechanism that is involved in
protection can be accompanied by an enhanced activity of a
different protective system.
A recent publication by Nebert (66) conceptualize how block
ing and suppressing activity might be brought about by the
same compound. This investigator discusses a possible relation
ship between components of the nuclear receptor superfamily,
with foreign chemicals as ligands, and cell proliferation. The
mouse peroxizome proliferator-activated
receptor, a novel
member of the nuclear receptor superfamily, has foreign chem
icals as its only ligands (67). Numerous studies show that
peroxizome proliferation is associated with liver carcinogenesis.
Relationships are proposed between the level of activity of drugmetabolizing (foreign body-metabolizing) enzymes, the steadystate level of small oxygenated molecules (including steroids)
that act as signals for growth, differentiation, and possibly
tumor promotion. If such interactions exist, opposing systems
might exist as well. One would entail inhibition of the activity
of the drug-metabolizing systems and a decrease in signals for
cell proliferation. Although these conjectures are highly spec
ulative, they form the conceptual basis for relating the activity
of systems that detoxify chemical carcinogens to nuclear control
mechanisms of cell proliferation. If a defense mechanism with
both blocking and suppressing components exists, it could be
triggered by a receptor mechanism.
A second possibility that might account for a compound
having both blocking and suppressing activity is high reactivity
with multiple effects due to this attribute. In such cases, block
ing and suppressing effects would be triggered separately. Ar
omatic isothiocyanates are highly reactive compounds and their
capacity to act as both blocking and suppressing agents might
be due to their high chemical reactivity. In contrast, D-limonene
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NONNUTRIENT
INHIBITORS OF CARC1NOGENESIS
is not a highly reactive molecule. However, it is metabolized to
epoxides that are highly reactive. The paucity of data makes it
difficult to evaluate the two major mechanisms of action con
sidered. If a receptor activating both blocking and suppressing
action were identified, it would be a major achievement. Even
if such a unified defense system does not exist, knowledge about
the characteristics of inhibitors having both blocking and sup
pressing effects might enhance the possibility of obtaining
chemopreventive agents with maximum protective capacities.
Summary
Epidemiológica! studies have shown that diets containing
large quantities of vegetables and, to a lesser extent, fruits are
associated with relatively low risks from cancer. The informa
tion about which constituents of these foods are responsible for
protection has been indecisive. One group of inhibitory com
pounds currently under investigation consists of minor nonnutrients in diets. Foods of plant origin frequently contain
amounts of these substances as high as several per cent. In
recent years there has been a growing awareness that these
nonnutrient compounds may have important effects on the
consequences of exposure to carcinogenic agents. This infor
mation comes from studies of whole diets; studies of individual
dietary constituents, particularly those of plant origin; and a
large number of investigations with pure compounds. The nonnutrient inhibitors of carcinogenesis have several different
mechanisms of action. Some are blocking agents; i.e., they
prevent carcinogens from reaching or reacting with critical
target sites. Others are suppressing agents; i.e., they prevent
evolution of the neoplastic process in cells which otherwise
would become malignant. Occasionally the same compound
will show both mechanisms. As studies of the inhibitory capac
ities of nonnutrient dietary inhibitors of carcinogenesis con
tinue, a clearer picture of their potential impact in cancer
prevention will emerge. Pending definitive data and as a prac
tical consequence of the current state of knowledge, the basic
recommendation of the National Research Council, the Na
tional Cancer Institute, and the American Cancer Society that
the daily diet should contain generous amounts of vegetables
and fruits should be followed. For individuals of sufficient
socioeconomic status, following this recommendation is a mat
ter of education and choice. For the economically deprived,
making available diets that decrease the risk of cancer involves
a public health concern.
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