Chemoprevention of Cancer...Chemoprevention of Cancer Lee W. Wattenberg Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455 Chemoprevention

[CANCER RESEARCH 45, 1-8, January 1985]

Perspectives in Cancer Research

Chemoprevention of Cancer

Lee W. WattenbergDepartment of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455

Chemoprevention of cancer is a means of cancer control inwhich the occurrence of this disease is prevented by administration of one or several chemical compounds. This Perspectivedeals with the areas in cancer control that this field addresses,the promise that it holds, and the problems that must be solvedin order to realize its goals. The most desirable way of eliminatingthe impact of cancer in humans is by prevention. The first set ofstrategies for achieving this objective is to remove the causativeagents. In some instances, as with cigarette smoking, it ispossible to eliminate the etiological agent. However, in others itis not. The causes of most cancers in the human are not known.Under some circumstances, even when causative factors areknown, neoplasia may have been initiated, and prevention nowfalls into the realm of suppressing the evolution of the neoplasticprocess. Individuals already exposed to carcinogens fall into thiscategory as do individuals at high risk to cancer because ofgenetic factors. Finally, there are a considerable number ofsuspect carcinogens in the environment that have been identifiedby virtue of mutagenicity testing. Many of these mutagenicsubstances occur in food. The carcinogenic potential of thesecompounds for the human is not clear. If they do in fact play arole in the occurrence of cancer, it would be exceedingly difficultto remove them from the environment. Flavones in food are anexample of a class of compounds that are mutagenic and thatwould be virtually impossible to remove because of their ubiquitous distribution. Likewise, if exposure to oxygen radicals andepoxides poses a hazard, as has been suggested by someinvestigators, such exposures would be difficult to prevent. Whileremoval of causative agents is the primary goal of cancer prevention, for the foreseeable future it is likely to be incomplete.Accordingly, the development of a second line of preventionbased on Chemoprevention assumes considerable importance.

The human constituencies that would be the target forChemoprevention vary. Two extremes are apparent, but in alllikelihood a continuum exists between them. At one extreme areindividuals at very high risk of developing cancer because ofgenetic predisposition or exposure to carcinogens. At the otherend of the risk spectrum are individuals lacking any evidence ofan increase in risk factors. The strategies for dealing with groupsat varying risks differ. As the risk for developing cancer increases,the compounds likely to be most effective are those that suppress evolution of the neoplastic process. The permissible riskof toxicity from the chemopreventive agent also will increase. Incontrast, when one considers chemopreventive agents to bedirected at populations with no enhanced risk from cancer,protection against attack from compounds that are involved inthe causation of cancer assumes a greater importance. For this

Received July 30, 1984; accepted September 26, 1984.

population group, little risk of toxicity from a chemopreventiveagent can be justified. Thus, when one evaluates a chemopreventive compound, considerations of its projected use are highlyrelevant. If the compound is very potent but has significanttoxicity, it may nevertheless be useful for high-risk individuals

but not for the general population. If a compound has modestprotective effects and little toxicity, considerations of its primaryuse for individuals at lesser risk to neoplasia would be appropriate.

ChemopreventiveCompounds

One of the most impressive findings in the field of Chemoprevention is the very large number of compounds that have beendemonstrated to prevent the occurrence of cancer. Compoundsbelonging to over 20 different classes of chemicals have beenshown to have chemopreventive capacities (Tables 1 and 2). Thegreat chemical diversity is a positive feature in that it indicatesthe likelihood that a variety of approaches can be made toprevention and that the options for selecting optimal compoundswill be large. Some of these inhibitors are naturally occurringconstituents of food (Table 1). Chemopreventive agents can beplaced into 2 broad categories. The first category includes compounds that are effective against complete carcinogens. Thesecond includes compounds effective against tumor promoters.Some compounds fall into both categories. As more data becomeavailable, this organization will almost certainly be modified.Nevertheless, it is useful for the present.

InhibitorsEffectiveagainstCompleteCarcinogens

The mechanisms of action of most inhibitors of carcinogenesis,both synthetic and naturally occurring, are poorly understood.This lack of information makes it difficult to organize them into acohesive pattern. One means of providing an organizationalframework is to classify inhibitors according to the time in thecarcinogenic process at which they are effective. Utilizing thisframework, inhibitors of carcinogenesis can be divided into 3categories (Chart 1). The first consists of compounds that prevent the formation of carcinogens from precursor substances. Inthe second are compounds that inhibit carcinogenesis by preventing carcinogenic compounds from reaching or reacting withcritical target sites in the tissues. These inhibitors are called"blocking agents," which is descriptive of the mechanism of

action. They exert a barrier function. A third category of inhibitorsacts subsequent to exposures to carcinogenic agents. Theseinhibitors are termed "suppressing agents" since they act by

suppressing the expression of neoplasia in cells previously exposed to doses of a carcinogenic agent that will cause cancer.

Compounds Inhibiting the Formation of Carcinogens. Amajor focus of this group of inhibitors has been on prevention ofthe formation of nitroso carcinogens from the reactions of pre-

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CHEMOPREVENTION OF CANCER

Table 1Inhibitors of carcinogen-induced neoplasia

Category ofinhibitorCompounds

preventingformationofcarcinogen fromprecursorcompoundsBlocking

agentsSuppressing

agents.Chemical

classReductive

acidsTocopherolsPhenolsPhenolsÃndolesAromatic

isothiocyanatesCoumarinsFlavonesDithiothionesOiterpenesDithiocarbamatesPhenothiazinesBarbituratesTrimethylquinolinesRetinoids

andcarotenoidsSelenium

saltsProtease

inhibitorsInhibitorsof arachidonicacidmetabolismCyanates

and isothiocyanatesPhenolsPlantsterolsMethylatedxanthinesOthersInhibitory

compoundsAscorbicacid8o-Tocopherol,8y-tocopherol8Caffeic

acid,8 ferulteacid,8Gallic

acid, propylgallate2(3Hert-Butylhydroxyanisote,i>

butylatedhydroxytoluene,"hydroxyanisole.ellagic acid,8 caffeic acid,8 ferulicacid,8p-hydroxycinnamic

acid,8 andotherslndote-3-acetonitrite,8indote-3-carbinol,83,3'-diindolymethane8Benzyl

isothiocyanate,8 phenethyl isothiocyanate,8 andphenylisothiocyanateCoumarin,

limettin80-Naphthoflavone,

o-naphthoflavone, quercetin pentamethylether*5-(2-PyrazinylH-methyl-1

,2-dithtol-3-thione,3-(p-methoxyphenyl)-1,2-dithtol-3-thioneKahweol

paknitate8Tetraethylthiuram

disulfide (disulfiram),sodiumdiethyldithiocarbamate.bis(ethylxanthogen)PhenothiazinePhÃ©nobarbital6-Ethoxy-1

,2-dihydrc-2,2,4-trimethylquinoline(ethoxyquin)Retinyl

palmitate,8 retinyl acetate,8 13-c/s-retinoic acid,ethylretinamide,

2-hydroxyethylretinamide, retinyl methyl ether,A/-(4-hydroxyphenyijretinamide.other synthetic retinoids,/3-caroteneSodium

selenite,* selenium dioxide* selemous ackj,8sodiumsetenideLeupeptin,

antipain, soybean proteaseinhibitors8Indomethacin,

aspirinSodium

cyanate, fert-butyl isocyanate, benzyl isothiocyanate82(3)-fert-ButylhydroxyanisoteD0-Sitosterol8Caffeine"Dehydroepiandrosterone,

fumarie acid8Refs.31,323821,3824,

34, 44, 56, 67.69,71-73,756866,686810.66,77a71,766867,69826733,

45, 48,52-544,

14, 17, 18,2816,41,8325,

35,3770

27,7583922,46

8 Naturally occurring compound present in food." Synthetic antioxidant used as a food additive." The closely related compounds tangeretin and nobiiitin occur in citrus fruits.

E. Bueding, unpublished results.

cursor amines or amides with nitrite. Ascorbic acid is effective ininhibiting formation of these carcinogens both in vitro and in vivo(31, 32). Animals given appropriate precursor compounds formnitroso carcinogens in vivo and subsequently develop neoplasms. Under these conditions, addition of ascorbic acid to thediet will prevent formation of the nitroso compounds and theoccurrence of neoplasia. Â«-Tocopherol and phenols also have

the capacity to inhibit formation of nitroso compounds (Table 1).A somewhat different type of inhibition potentially can occur

within the large bowel. The large bowel flora can form electrc-philes from precursor compounds. In one such study, 4-isothio-cyano-4'-nitrodiphenylamine was fed to 6 species of animals. In

each instance, the large bowel flora converted the parent compound to a mutagen. This did not occur in germ-free rats and

could be prevented in animals with a normal microbial flora byadministration of antibiotics (1). In humans, the fecal flora produces mutagenic compounds termed fecapentaenes (15, 60).The implication of these mutagens for humans has not beenestablished. If they do represent a hazard, their synthesis potentially could be controlled by compounds altering availability ofprecursor compounds or modifying the intestinal microbial flora.

Blocking Agents. General Consideration. Blocking agentsprevent carcinogens from reaching or reacting with critical targetsites. A large and diverse group of compounds both naturallyoccurring and synthetic falls into this category of inhibitors (Table1). An understanding of their mechanisms of action is based on

the contributions of the Millers and others to the field of chemicalcarcinogenesis (29, 30). A vast amount of information has beenaccumulated which demonstrates that chemical carcinogens actvia common mechanisms. The ultimate carcinogenic forms ofcarcinogens are positively charged electrophilic species. Somecarcinogens, termed "direct acting," exist in this form or assume

it in solution. Others require metabolic activation. Blocking agentscan be placed into 3 groups according to their mechanism ofaction. One group acts simply by inhibiting the activation of acarcinogen to its ultimate carcinogenic form. An example of thistype of inhibition is the prevention of symmetrical dimethylhydra-zine-induced neoplasia of the large bowel by disulfiram (65). Thiscompound inhibits the metabolism of symmetrical dimethylhydra-

zine to its carcinogenic metabolites (11). Inhibitors in this groupare effective only against carcinogens requiring activation. Asecond group of blocking agents is effective by virtue of inducingincreases in activity of enzyme systems having the capacity toenhance carcinogen detoxification. The inhibitors in this groupare of particular interest because they have the capacity to inhibita wide range of carcinogens. They will be discussed more indetail in the next paragraph. The third group of blocking agentshas the capacity to act by scavenging the reactive forms ofcarcinogens. Physiological nucleophiles, such as GSH,1 fall into

1The abbreviations used are: GSH, glutathione; BP, benzo(a)pyrene; DMBA,7,12-dimethylbenz(a)anthracene; TPA, 12-O-tetradecanoylphorboM3-acetate.


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Table2Inhibitors of tumor promotion of the mouseskin

Classof inhibitor Compound Refe.

Retmoids

Proteaseinhibitors

Inhibitorsof arachidonicacidmetabolism

Phenols

SyntheticcompoundwithSuperoxidedismutaseactivity

Cyclicnucleotidesorinhibitorsofphosphodiesteraseactivity

All-trans-retinoic acid, 13-cis-retinoic 62,63acid, ethyl-9-(4-methoxy-2,3,6-trimetriy1pnenyl)-3,7-dimethyt-irar7S-2,4.6.8-nonatetraenoate

Tosyl lysine chloromethyl ketone 57,59Tosylargininemethylester 57,59Tosylphenylalaninechloromethyl 57,59

ketoneLeupeptin 16

Dexamethasone 57,625,8,11,14-Eicosatraynoic acid 13Fluocinolone acetonide 47Fluocinonide 64Fluclorolone acetonide 64Indomethacin 64Nordihydroguaiaretic acid 361-Phenyl-3-pyrazoledinone 13p-Bromophenacyl bromide 36

Dibromoacetopnenone 13

p-Methoxyphenol 492-(ert-Butylhydroxyanisole ' 49

3-tert-Butylhydroxyanisole 49

Copper(ll) 3,5-diisopropylsalicylic acid 20,50

CyclicAMP3-lsobutyl-1 -methyl xanthene

42

PolyaminesModulation

of calciummetabolismBenzodiazepinesOthersPutrescine1

a, 25-Dihydroxy vitaminD3DiazepamQuercetin,

o-difluoromethylomithine78801219,55

this group. Recently, xenobiotic compounds present in plantconstituents of the diet have been shown to scavenge theultimate carcinogenic form of BP. Ellagic acid has been shownto be highly potent in this regard (81). Among compounds thatcan scavenge carcinogens, one group is potentially of considerable interest, namely, those that would be effective in inhibitinggastrointestinal neoplasia. High-molecular-weight compounds

that are not absorbed from the gastrointestinal tract and accordingly could scavenge the reactive form of carcinogens occurringwithin the lumen of the alimentary tract fall into this category.

Blocking Agents That Increase the Activity of Systems ThatCan Enhance Carcinogen Detoxification. One group of blockingagents that inhibit chemical carcinogens induces multiple enzymatic alterations. Before proceeding to further considerations ofthese inhibitors, a brief discussion of detoxification of xenobioticcompounds is relevant. In general, the overall metabolism offoreign compounds is directed towards producing chemical species that can be excreted. Two classes of enzyme systems havebeen proposed by Williams (79) for the metabolism of xenobioticcompounds to excretory metabolites. These are termed Phase Iand Phase II reactions. Phase I reactions introduce polar groupsinto xenobiotic compounds. Most are oxidative reactions. A feware reductive. The enzyme system most frequently involved isthe microsomal monooxygenase system. The presence of a polargroup on a xenobiotic compound provides a means by which a

CATEGORY OFINHIBITORS

SEQUENCE LEADINGTO NEOPLASIA

Precursor Compounds

Inhibitors PreventingFormation of Carcinogens

Carcinogenic Compounds

Blocking Agents

Reactions withCellular Targets

Suppressing Agents

Neoplastic ManifestationsChart1. Classificationof chemopreventiveagentson the basisof the timeat

whichtheyexerttheirprotectiveeffects.

subsequent conjugation reaction can occur, leading to excretion.Phase II reactions, for the most part, are conjugating reactionssuch as formation of glucuronides, GSH conjugates, and sulfates. The reactions detoxifying foreign compounds are exceedingly important in preventing toxidty from a wide variety ofxenobiotic compounds including chemical carcinogens. With thevast variety of reactions catalyzed by the Phase I and Phase IIenzymes, it might be anticipated that some adverse reactionsoccur. Such is the case, but overall this complex system is highlyprotective (67, 68).

Two general categories of blocking agents that enhance carcinogen detoxification systems have been identified in studies ofinhibition of carcinogenesis. They are designated type A andtype B inhibitors. Others almost certainly exist. In many instances, insufficient data are available to classify a particularinhibitor as being type A or type B. Both type A and type Binhibitors induce an increase in activity of multiple enzymes,presumaby by reacting with receptors. A receptor has beendemonstrated for some type B inhibitors but not as yet for typeA inhibitors (43, 69, 71). The induction of increases in activity ofmultiple enzymes with coordinated function is in accord with areceptor mechanism. The type A inhibitors induce an increase inPhase II enzymes, i.e., conjugating enzymes and some relatedsystems (71). A prominent feature of these enzymatic inductionsis a marked increase in GSH S-transferase activity (2,3,7). UDP-

glucuronosyltransferase activity is also enhanced as is epoxidehydrolase and NAD(P)H-quÂ¡nonereducÃaseactivity (5, 6). Other

features of type A inhibitors include an alteration in microsomalmetabolism in which there is little change in activity but a pronounced alteration in metabolite pattern as demonstrated withBP as the substrate (23). In addition to enzymatic changes, anincrease in the levels of GSH in tissues is also found (1,2). TypeA blocking agents have been shown to inhibit carcinogenesisresulting from administration of BP, BP-7,8-dihydrodiol, DMBA,dibenz(a,/7)anthracene, diethylnitrosamine, 4-nitroquinoline A/-OX-

ide, uracil mustard, urethan, methylazoxymethanol acetate, andfrans-5-amino-3-[2-(5-nitro-2-furylvinyl)]-1,2,4-oxadiazole (69).

Type B inhibitors characteristically induce pronounced increases in microsomal monooxygenase activity. A prototype ofthis class of inhibitors is /3-naphthoflavone. Subclasses existdependent upon differences in the species of cytochrome P-450

induced. Type B inhibitors also enhance the activity of major


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conjugating systems such as GSH S-transferase and UDP-glu-

curonosyltransferase. Type B inhibitors have been shown toinhibit the occurrence of neoplasia resulting from administrationof BP, DMBA, 3'-methyl-4-dimethylaminoazobenzene, A/-2-flu-

orenylacetamide, 4-dimethylaminostilbene, urethan, and afla-toxin (68). These inhibitors are complicated in that the microso-

mal monooxygenase system can both activate and detoxifychemical carcinogens. The classic example of this is with thearomatic amines. With these compounds, ring hydroxylationresults in detoxification, whereas hydroxylation of the nitrogenis an activation reaction. In most instances, when tested inexperimental animals, type B inhibitors have been found to inhibitchemical carcinogenesis (68). Presumably, the overall inductiveeffects on both Phase I and Phase II systems in aggregate resultin enhanced carcinogen detoxification. However, the fact thatone component of the enzyme induction can increase carcinogenactivation makes it possible that conditions may exist in whichenhancement of carcinogenesis might occur. A concern withboth type A and type B inhibitors is that the particular compoundwill have multiple biological effects, some of which are noxious.

The resolution of the implications for the human of blockingagents that act by virtue of enzyme induction is likely to residein 2 areas. The first is epidemiology. Since a large number ofthese blocking agents are naturally occurring constituents offood, it may be possible eventually to assess the role that thesecompounds play in inhibiting the occurrence of neoplasia inspecific population groups. The second is likely to come frommuch more effective basic experimentation than has been carriedout thus far on the mechanism(s) of enzyme induction. Asdiscussed above, there is evidence that this class of inhibitorsacts by virtue of reacting with receptors. If this is the case, thenthe critical information will reside in defining the specific responses to activation of particular receptors and the structuralcharacteristics of the ligands for these receptors. With suchinformation, one might be able to design ligands with minimal orno other biological effects, particularly adverse ones. In addition,the potential would exist for selecting the receptor providing themost favorable aggregate of enzyme responses appropriate formaximum detoxification capacity and minimum for confoundingnoxious side effects.

Detection and Identification of Blocking Agents. Blockingagents that act by virtue of their ability to inhibit activation of acarcinogen to its ultimate carcinogenic form can be detected bystudies of the effects of test compounds on the activatingsystem. Initial work of this type can be done with in vitro systems,but ultimately it is necessary to determine the effects of the testcompounds in vivo (11). The blocking agents that act by inhibitingenzymatic activation of carcinogens are relatively specific. Incontrast, inhibitors that act by virtue of their capacity to induceincreased activities of multiple enzymes with the capacity todetoxify chemical carcinogens have been shown to inhibit a widevariety of carcinogens. The diverse chemical structures of blocking agents that act by this type of mechanism indicate thatcompounds in addition to those already identified will almostcertainly exist. A means of identifying these inhibitors in complexmixtures such as dietary constituents is by virtue of the capacityto induce increased activity of enzymes that can detoxify chemical carcinogens. This is particularly true for induction of PhaseII enzymes which is a characteristic of both type A and type Binhibitors. Induction of increased GSH S-transferase activity by

crude materials and the subsequent identification of the inducingcompounds using GSH S-transferase induction as an assay

system for monitoring the purification process has been usedsuccessfully for identifying new blocking agents (71, 76).

The detection and identification of blocking agents that act byvirtue of their capacity to trap reactive species of carcinogenscan be identified by several techniques. One of these is todetermine the specific reaction of the putative inhibitor with thecarcinogen as has been done with ellagic acid and BP-7,8-diol-9,10-epoxide (81). A more general type of testing entails the

inhibition of binding of the carcinogen to DNA by the test compound. Inhibition of mutagenesis in the Ames system can alsobe used. Ultimately, in vivo studies should be performed sincethe complex conditions occurring in vivo may be very differentthan those existing for in vitro test systems.

Suppressing Agents. Suppressing agents are compoundsthat inhibit carcinogenesis when administered subsequent to acourse of carcinogen administrations that would result in theoccurrence of cancer. The number of classes of compounds thatact as suppressing agents is smaller than that of blocking agents.Unlike the situation existing for blocking agents, there are nogeneric short-term test systems indicating the likelihood that a

compound is a suppressing agent. Thus, they are more difficultto identify. The most extensively studied suppressing agents arethe retinoids. These compounds have been reviewed recently(33,52-54). There are several salient points that should be made

concerning the retinoids: they can be highly effective as suppressing agents; individual retinoids target to specific tissuesrather than on all tissues (some tissues such as the large bowelappear to be particularly refractory); in general, the effects of theretinoids are reversible; the compounds have toxic properties;and their mechanisms of suppressing action have not beenclearly elucidated. The current status of information about thesecompounds indicates that they are likely to be most suitablyutilized for groups or individuals at high risk to the occurrence ofcancer. Major efforts are in progress worldwide to produce moreeffective retinoids and to determine their mechanism or mechanisms of action. (9-Carotene, which can be metabolized to retinol,has been reported to have a suppressive effect on DMBA-

induced mammary neoplasia (45, 47).Selenium salts are an exceedingly interesting group of sup

pressing agents. These compounds have been found to inhibit aconsiderable variety of experimental neoplastia systems. Included are the inhibition of virus-induced neoplasia of the mam

mary gland in mice as well as carcinogenesis resulting fromadministration of chemical carcinogens to both mice and rats (9,14, 18). EpidemiolÃ³gica! data have been interpreted by someinvestigators as indicating that a low selenium consumption mayincrease the occurrence of neoplasia in certain human populations (9). There are 2 pressing problems in the available information concerning selenium inhibition of neoplasia. The first hasto do with the mechanism or mechanisms by which seleniumacts. Unfortunately, very little information exists on the mechanism^) by which selenium inhibits the occurrence of neoplasia.The second problem, which is related, concerns the relationshipsbetween species, dose, and effectiveness of selenium as aninhibitor. Good information on the relationships of dose to protection against neoplasia is not available for different species ofexperimental animals and likewise for the human. Since seleniumcan have toxic effects, a major defect in currently available


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information is the inability to predict the dose level in the humanthat would give maximum protection without producing toxicity(9). Dehydroepiandrosterone is an interesting inhibitor in that ithas been shown to suppress neoplasia in several experimentalsystems (46). the mechanism of this suppression is not known.The number of investigators who have carried out experimentswith this and related compounds as inhibitors of carcinogenesishas been very small. The use of protease inhibitors and inhibitorsof arachidonic acid metabolism as inhibitors of carcinogenesis isunder investigation by several groups of workers. The numberof target sites at which inhibition has been demonstrated isrelatively small for both of these classes of compounds as wellas other remaining suppressing agents listed in Table 1.

A series of experiments has been published recently by Nomura ef al. (40) showing that caffeine, antipain (a proteaseinhibitor), and retinoic acid can inhibit urethan-induced terato-

genesis and in some instances teratogenesis resulting fromadministration of other carcinogens. Information concerning anycommon features between the mechanisms of suppression ofneoplasia and teratogenesis could prove to be of importance.

Compounds Inhibiting Tumor Promotion

In Table 2, 9 classes of compounds that inhibit tumor promotion are listed. In some instances, a class contains a sizablenumber of inhibitors; and in others, there is one compound. Thevast majority of these studies have focused on inhibition ofpromotion of epidermal neoplasia in the mouse as a result oftopical administration of TRA. A few studies have used othertumor promoters. Of particular interest in this latter group havebeen experiments in which the tumor promoter used was benzoylperoxide. A major hypothesis concerning tumor promotion hasbeen that attack by oxygen radicals may play a role in itscausation (49, 58). In accord with this hypothesis has been thedemonstration of oxygen radical formation in the mouse epidermis following application of TPA. Several groups of inhibitorsthat overall prevent attack by oxygen radicals inhibit tumorpromotion. Phenolic antioxidants inhibit tumor promotion by benzoyl peroxide (49). Protease inhibitors prevent formation of oxygen radicals by TPA and inhibit tumor promotion (58). A synthetic compound with Superoxide dismutase activity, i.e., cop-per(ll) 3,5-diisopropylsalicylic acid, inhibits tumor promotion (20,

50). Thus, there is a body of evidence indicating the possibilitythat one mechanism of inhibition of tumor promotion may residein a "blocking action" in which the tissues are protected from

attack by oxygen radicals.A comparison of compounds listed in Tables 1 and 2 show

that members of 3 major groups, i.e., retinoids, protease inhibitors, and inhibitors of arachidonic acid metabolism, which havethe capacity to act as suppressing agents following administration of a full course of carcinogens also are inhibitors of TPA-

induced promotion of epidermal neoplasia. An example of theformer type of experiment is one in which a single dose of DMBAis given to Sprague-Dawley rats and inhibition is brought about

by feeding a retinoid in the diet starting 1 week after the administration of the carcinogen (33). An example of inhibition of TPA-

induced tumor promotion by a retinoid entails the administrationof the retinoid prior to each of multiple administrations of TPA tothe skin of the mouse (62). The observation that members of 3major groups of inhibitors will inhibit the occurrence of neoplasia

in both types of experimental models suggests the possibility ofsome common mechanism. Studies of inhibition of tumor promotion in target tissues other than skin and with a variety oftumor promoters are badly needed.

Compounds Inhibiting Neoplasia When Administered Shortlybefore Exposure to a Carcinogenic Compound

Compounds that exert inhibitory effects when administeredshortly before exposure to a compound involved in the causationof cancer have implications that merit separate consideration.Some inhibitors are effective if administered during a time intervalranging from several minutes to several hours prior to the cancer-

causing agent. In interpreting epidemiological data as well as forconsideration of deliberate intervention strategies, short-time

interval effects could be of importance. In general, epidemiological studies of the relationships of diet to cancer do not deal withthe sequence in which foods are consumed. Thus, if a protectivesubstance was eaten at the beginning of a meal (an "inhibitoryhors d'oeuvre") and a carcinogenic compound, i.e. an initiator or

promoter, is consumed later in the meal, the likelihood of protection would be greater than if the reverse sequence of consumptions occurred. Likewise, for considerations of deliberate intervention, rapidly acting inhibitors could protect against constituents of the diet that might be involved in the causation ofneoplasia. In Table 3 are listed compounds that inhibit full carcinogens when administered shortly before the carcinogen. In addition, there are a number of compounds that inhibit tumorpromoters when administered shortly before the promoter.These include all-frans-retinoic acid, 13-cis-retinoic acid, ethyl-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-frans-2,4,6-non-atetralnoate, dexamethasone, fluocinolone acetonide, flucloro-lone acetonide, nordihydroguaiaretic acid, p-bromoacyl bromide,coppelli) 3,5-diisopropylsalicylic acid, p-methoxyphenol, 2-tert-butylhydroxyanisole, 3-fert-butylhydroxyanisole, cyclic AMP, and3-isobutylmethylxanthine (20, 36, 42, 47, 49, 50, 62-64).

Discussion

There are a large number of compounds that can prevent theoccurrence of cancer. The number of experiments that havebeen performed that show this end result is of the order ofseveral hundred. The chemical diversity of the inhibitors indicatesthat inhibition of carcinogenesis is not a highly selective phenomenon and that multiple strategies exist for bringing about thisdesired effect. It also makes it probable that additional compounds with chemopreventive properties will be identified in the

Table 3

Inhibition of carcinogenesis by compounds administered shortly before exposureto the carcinogen

Inhibitor7,8-Benzoflavone2(3)-fert-Butylhydroxy-anisole4-MethoxyphenolBenzyl

Â¡sothiocyanateKahweol

palmitateCarbon

disulfideCarcinogenDMBABP/3-PropiolactoneDMBADMBASymmetricaldi-methylhydrazineSpeciesMouseMouseMouseRatRatMouseOrganSkinLungForestomachMammaryglandMammaryglandLargeintestineRef.10,6151726671,7674


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future, again adding to the choices that wilt be available. Thesedata enhance the likelihood that chemoprevention of neoplasiawill prove of value as a method of cancer control in the human.Given this favorable outlook, where are we now and how do weprocede most effectively?

In terms of application of existing information to prevention ofcancer in the human, there has been a focus on 2 types ofefforts. One of these has been to select compounds that havevery little toxicity and to use these in an attempt to preventneoplasia in selected populations. Three such compounds fallinto this category. These are ascorbic acid, a-tocopherol and ÃŸ-

carotene. The hope has been that these compounds could beadministered with very little risk to human subjects and that theywould produce a significant preventive effect. In experimentalsystems for evaluating inhibition of carcinogenesis, these compounds have not been shown to have broad inhibitory capacities.Ascorbic acid is effective in preventing the formation of nitrosocarcinogens from precursor compounds but in most instances isnot effective in inhibiting carcinogenesis resulting from administration of preformed carcinogens (31, 32). There is only a smallamount of published evidence showing inhibition of carcinogenesis by a-tocopherol, in spite of the fact that this compound has

been investigated for its inhibitory effects over a long period oftime (67). Only a few studies of inhibition of carcinogenesis by0-carotene have been reported. These have shown inhibition of

mammary neoplasia in the rat and epidermal neoplasia in themouse (26, 45, 48). Thus, while the risk of the use of thesecompounds would appear to be minimal, it is quite possible thattheir administration to humans will not show positive results. Ifthis proves to be the case, recognition should be made of theconsiderations involved in their early choice for studies in thehuman. These negative results should not discourage furtherendeavors to explore the use of more effective chemopreventivecompounds.

The second focus has been on the retinoids. This group ofcompounds has inhibitory efficacy in experimental animals butalso can produce toxic reactions. Accordingly, they have beenselected for use in populations at increased risk to neoplasia.Evaluation of the effectiveness of some retinoids for preventionof neoplasia in humans is currently in progress. Substantialefforts are being made to elucidate their mechanism(s) of inhibition and to develop more effective analogues. The retinoids,however, are a special case. Nothing approaching the effortsdirected at the development and application of retinoids aschemopreventive agents exists for other categories of inhibitors.

A common situation existing for many of the inhibitors identified thus far is that: (a) the inhibitors being studied experimentallyare first-generation compounds; i.e., these are the compounds

which originally were shown to be inhibitory and little work onother analogues exists except perhaps for a few that are readilyavailable; (b) little is known about the mechanism of inhibition;and (c) the number of investigators working on the compound issmall, in some instances a single individual. This combination ofevents is not favorable for the development of the field. The useof first-generation compounds means that there is not a clearperspective on some major attributes of the particular categoryof inhibitor. A number of first-generation inhibitors have noxious

properties. One does not know whether these are necessarilyassociated with the inhibitory property of the compound or arean unrelated biological characteristic that could be dissociated

from the essential inhibitory mechanism of the compound bystructural modification. In a number of instances, high concentrations of a compound are required for inhibitory effects. Again,working with a first-generation compound, one does not know

whether this is a characteristic of the particular inhibitor orwhether structural modification would result in a significantlymore potent compound. Thus, with first-generation inhibitors,

we lack knowledge of maximum efficacy and minimal toxicity ofthe particular type of compound. An additional critical deficiencyin our knowledge about inhibitors of carcinogenesis is the paucityof the data on their mechanisms of action. Information of thisnature is an essential ingredient of an effective program.

The field of chemoprevention of cancer requires considerablefurther expansion. The leadership of the National Cancer Instituteand the American Cancer Society have made major commitments, intellectual and resource, to this field. One would hopethat these will be continued and perhaps enlarged. There is onefurther way in which the information base can be expandedeffectively. It entails a conceptual commitment by investigators.When an investigator works on a mechanistic problem relatedto the causation of cancer, whether this be the metabolism andtargeting of a chemical carcinogen, the consequences of anoncogene expression, or any of the numerous other investigations of mechanism, the question should be asked "How can

this process be inhibited or suppressed so as to prevent theoccurrence of cancer?" If this question were asked and followed

by appropriate experimentation when feasible, it would converta large group of experimental oncologists into major contributorsto developing means for cancer prevention.

The essence of the present Perspective can be summarizedquite briefly. Chemoprevention can readily protect experimentalanimals against the occurrence of neoplasia. We now must learnhow to bring this protection about effectively for the human.

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Chemoprevention of Cancer...Chemoprevention of Cancer Lee W. Wattenberg Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455 Chemoprevention