[CANCER RESEARCH 35, 3292-3300November 1975]

Summary

Restriction of the total diet or the number of calories fedto rats and mice inhibits the formation of tumors in severaltissues. Unless animals are fed equivalent levels of food, orattain equivalent body weights, it is difficult to assess thesignificance of the effect of other nutritional modificationson carcinogenesis. The effects of altering the levels ofprotein or fat are much less than those seen with dietaryrestriction. Feeding a protein-free diet is tolerated for alimited period and can alter the metabolism of carcinogens.It may thus affect the tumor incidence induced by one-shotcarcinogens. Vitamins have specific effects on the activity ofcertain carcinogens, the fullest information being availablefor vitamin A, which has been shown to inhibit or enhancecarcinogenesis, and vitamin C, which by reducing sodiumnitrite, prevents nitrosation of secondary and tertiaryamines occurring in acidic conditions of the stomach.Inorganic substances, such as iodine (thyroid) and copper(liver), may affect the tumor incidence in specific tissues.The metabolic activation of carcinogens is modified byenzyme induction and the administration of antioxidants.The relevance of these results to the induction of cancer inhumans is briefly discussed.

Introduction

Carcinogenesis may be affected by nutrition in 2 ways.Food or drink may be contaminated by carcinogens, or thecomposition of the diet may impose upon the host patternsof enzyme activity and other factors that dictate the yield ofnaturally occurring or induced tumors. The deliberateaddition of carcinogenic additives to food should diminish,as a result of worldwide governmental action. Nevertheless,the control of naturally occurring carcinogens in foodpresents difficulties, especially for technically developingcountries. The most studied naturally occurring carcinogensinclude aflatoxins B1 and G1, sterigmatocystin, and othermycotoxins (40). There is presumptive evidence thataflatoxins are carcinogenic in humans (67). Also to beconsidered are the carcinogens present in bracken fern(20—22,64), cycasin (42), the nitrosamines, especially thoseformed from nitrite and secondary or tertiary amines (53,79), environmental goitrogens, and hormones, and otherdietary carcinogens. Besides their possible carcinogenicactions in man, the presence of these substances may

CPresentedattheConferenceonNutritionintheCausationofCancer,May 19 to 22, 1975,Key Biscayne,Fla. Supported by Contract NOICP33278from the National Cancer Institute, NIH, USPHS.

considerably modify the response of experimental animalsin carcinogenicity tests.

Changes in tumor incidence may also be brought aboutby altering the composition of the diet. In some cases,especially in that of chemical carcinogens, there is knowledge of the mechanism by which these changes arise.Modifications of the metabolic activation of carcinogens bycontrolling the levels of cofactors or by inducing differentpatterns of metabolizing enzyme activities are well documented. On the other hand, those factors which regulatetumor development, such as different levels of cellularproliferation or immunological control, do not appear tohave been as amenable to study.

This presentation will illustrate the way in which nutnitional differences can affect tumor incidence in experimental systems. Wherever possible, the mechanism by whichthese changes are mediated will be discussed.

Dietary and Caloric Restriction

The demonstration from actuarial records that overweight or obese men had a higher cancer mortality thannormal or underweight men led Tannenbaum (93) toinvestigate the effect on the development of spontaneousand induced tumors of a restricted dietary intake in mice.Dietary restriction reduced the incidence of mammarytumor virus-induced tumors in DBA and C3H mice,spontaneous lung tumors in Swiss and ABC mice, B(a)Pinduced skin tumors and, to a lesser extent, s.c. sarcomasinduced by B(a)P (Chait 1) (94, 95). Similar effects havebeen observed in rats. As in mice, underfeeding greatlyincreased the life-span (45) and led to a lower tumorincidence than that found in animals that received adlibitum supplements 74, 80). In these underfeeding studies,the amounts of the various dietary components werereduced proportionately to each other.

An alternative to underfeeding is caloric restriction, inwhich the amount of carbohydrate is reduced, while othercomponents are maintained at a constant level. Calorierestricted diets also lessen the incidence or delay theappearance of certain tumors, such as mammary tumors inDBA mice (Chart 2) (97). In this example, the inhibitionwas apparent, even if the restricted diet was not instituteduntil the mice were 9 months old.

The mechanism by which dietary restriction inhibits

2 The abbreviations used are: B(a)P, benzo(a)pyrene; DAB; 4-dimeth

ylaminoazobenzene; DMN, dimethylnitrosamine; MCA, 3-methylcholanthrene; DMBA, 7,l2-dimethylbenz(a)anthracene;FAA, N-2-fLuorenylacetamide;BHA, butylated hydroxyanisole; BHT, butylated hydroxytoluene.

CANCER RESEARCH VOL. 353292

Nutrition and Experimental Carcinogenesis: A Review'

David B. Clayson

Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska 68105

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A MAMMARY-DBAQMICEB SKIN-B(a)P INDUCEDC MAMMARY-C3H9MICE

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Nutrition and Experimental Carcinogenesis

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mediated through its effect on body weight. They suggestedthat the inhibition of tumorigenicity is associated with anoverall nutritional deficiency at the cellular level, but did notspeculate as to the nature of the process. Whatever theexplanation of these observations, they are crucial to allaspects of experimental tumorigenesis. Experiments designed to show anything more than the crudest tumor-inducing potency of a strong carcinogen must be carried out insuch a manner that all experimental and control groupsmaintain similar body weights. Experiments that fail toadhere to this principle are difficult to interpret. Factorsthat may lead to decreased body weight in treated animalsinclude chemical toxicity, unpalatability of the diet, andchronic ill health in the colony. Good experimentation canovercome these difficulties. Because the influence of dietaryand caloric restriction was not realized until 1940, work innutrition and cancer carried out before that time is difficultto interpret.

Protein Levels

The feeding of isocalonic diets containing levels of proteinranging from 9 to 45% failed to influence the incidence ofmammary tumors in DBA and C3H mice, and that ofhydrocarbon-induced skin tumors and s.c. sarcomas. Spontaneous hepatomas in C3H mice occurred less frequentlywhen the 9% protein diet was fed (100). This was due to adiminution in the concentration of the essential sulfur-contaming amino acids, cysteine and methionine. The additionof sufficient protein, freed from these amino acids, to raisethe protein level from 9 to 18%, failed to affect the incidenceof spontaneous hepatomas, whereas addition of the calculated amounts of these amino acids did so (88).

High protein levels, however, protect the rat liver againstcarcinogenesis by DAB. Adequate dietary casein, even withlow levels of riboflavin (see below) protects the rat liveragainst this chemical. The reason for this phenomenon isnot known. Tannenbaum and Silverstone (104) suggestedthat the high-protein diet might be protective because itenabled the liver to store and utilize riboflavin moreefficiently.

Ross and Bras (75) fed diets containing 10, 22, or 51%casein on either a restricted (equicaloric) or an ad libitum

Table I

MammarySkinTumors Carcinomas(24 weeks) (86weeks)

00

80

UzUaUz

g2I-1e 20-

-p

0- -

The dependenceof the genesisof induced skin tumors on the caloricintake during different stages of carcinogenesis°

aFromRef.95a F, full diet; R, restricted diet.

NOVEMBER 1975 3293

30— (24 weeks)

@2O— fl

@l:1@J@ L1= EL

@ :@ DIETadIsbitum@@ RestrictedDIETChart I . The effect of restricting caloric intake on the incidence of

sarcomas and skin tumors induced by B(a)P and on naturally occurringmammary tumors in DBA mice (95).

‘ 0 II 2 3 14CALORIC INTAKE per DAY

Chart 2. The effect of caloric restriction on mammary tumor induction

in C3H and DBA mice and on skin tumors inducedby B(a)P (98).

tumonigenesis is unknown. Initiation-promotion studies inskin carcinogenesis were said to show that restriction waseffective in the promotion or developmental stage of tumorformation, but some influence on the initiation stage couldnot be excluded by the data presented (Table 1) (97). Theyield of mammary tumors was not affected by starvingDBA. mice for 2 periods of 24 hr each week and permittingthem to eat ad libitum for the remaining time. These miceconsumed as much as those fed ad libitum continuously(101). The actual number of calories is not necessarilysignificant, because mice fed thyroid extract consumed 1.5times the normal amount, while maintaining a slightly lowerthan average body weight. The yield of tumors induced bypainting B(a)P on the skin was unaffected by thyroid extract(85). Other treatments, which did not involve reduction ofcaloric intake and reduced body weight, included maintaining the mice in a cold environment (7.2—12.8°)or feedingthem dinitrophenol or sodium fluoride. Each of thesetreatments significantly inhibited naturally occurring mammary tumors in DBA mice. The chemicals blocked formation of lung adenomas but had little effect on B(a)P-inducedsarcomas, while dinitrophenol showed little influence onB(a)P-induced skin tumors (99). Gold thioglucose induces aspecific hypothalamic lesion in mice which causes severeobesity through an increase in adipose tissue, leading to adoubling of the body weight. A high incidence of mammarytumors were obtained in these animals (113).

Tannenbaum and Silverstone (104) concluded that therelevant effect of dietary or caloric restriction was probably

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Regimen10%

casein20% casein5 1%caseinLife

expectancy

(days)Tumorbearing

rats (%)No.

ofbladder

papillomasLifeexpectancy

(days)Tumorbearingrats (%)No.

ofbladder

papillomasLifeexpectancy

(days)Tumorbearingrats (%)No.

ofbladder

papillomasAdlibitum

Restricted(equicaloric)540

69225.6 11.43 5585 83828.8 19.29 9614 93428.0 21.61913a

From Ref. 98.

D. B. Clayson

regimen to rats. Longevity increased from the group of ratsfed 10% casein ad libitum to that fed 51% casein restricted,and tended to increase with the amount of protein in thediet. The most common tumor in the high-protein groupswas papilloma of the urinary bladder (Table 2). Urinarystone formation was not described ( I3). Possibly, this is aneffect of the increase in the amount of the essential aminoacid tryptophan administered in the protein. It has beensuggested that the urinary output of those tryptophanmetabolites on the niacin pathway is higher in some patientswith nonoccupational bladder cancer than in normal subjects (9, 68). Furthermore, feeding a 7-fold excess ofDL-tryptophan to dogs led to hyperplasia of the urinarybladder (69). An increase in the proliferation of the ratbladder epithelium has been reported on a similar regimen(56). The metabolites of tryptophan responsible for theseeffects have not been identified. They might be N-hydroxylated derivatives of the amino acid and its metabolites. Thepreviously suggested o-aminophenol derivatives (68), whichhave, as yet, given little satisfactory evidence of biologicalactivity in the bladder, are unlikely to be the carcinogenicfactor.

Very low levels of protein can be sustained for shortperiods of time, but are not compatible with the survivalrequired for most carcinogenesis tests. The advent ofsingle-dose carcinogens has made it possible to maintainanimals on a very low protein diet during administration ofthe carcinogen and then return them to an adequate diet forthe remainder of their lives. Swann and McLean (92)showed that feeding a protein-free diet for only 7 days led toa 45% inhibition of liver metabolism of DMN in vivo, butthat kidney metabolism was unaffected. In liver slices, thispretreatment led to more than a 50% inhibition of metabolism. The amount of 7-N-methylguanine formed in liverRNA and DNA was little affected by the protein-free diet,while that in the kidneys increased 3-fold. The overall effectof the low-protein diet was to decrease hepatoxicity andincrease the dosage that is lethal to 50% of the animals,thereby enabling more chemical to be administered in asingle dose. Thus, by giving the maximum tolerated dose, itwas possible to increase the incidence of kidney tumorsinduced by a single administration of DMN (30, 46, 92).Very-low-protein diets or starvation for a limited period willprotect the liver from toxic or carcinogenic chemicals,because they induce a general reduction in the activity ofmicrosomal metabolizing enzymes 447). No effect of verylow-protein diets or starvation has been observed in the

induction of esophageal (107) or nasal epithelial tumors(62).

The possibility that protein from various sources mayinfluence carcinogenesis has not been studied. It may beminimal in view of the hydrolysis of protein to amino acidsbefore ingestion. Such experiments are required to assessthe significance, for example, of beef consumption in theetiology of human colon cancer (2).

Lipotrope Deficiency

Lipotropic substances are those which prevent or correctfatty liver due to choline deficiency. Lipotrope-deficientdiets are low in choline and methionine. Choline-deficientdiets per se in rats, and in chickens surviving beyond 78weeks, led to fatty livers and to liver tumors (17, 78). Morerecent confirmation of the latter result is lacking (58), andthe possibility cannot be excluded that the liver tumors werea consequence of the interaction of the hepatotoxic diet (59)and adventitious contamination with a natural carcinogen,such as aflatoxin B1. Nevertheless, there is evidence thatlipotrope-deficient diets enhance hepatoca rcinogenesis byaflatoxin B1, diethylnitrosamine, and DBN (58, 71). In thelatter 2 examples, the latent period of the tumors wasdiminished. Esophageal cancer induction by diethylnitrosamine was possibly also enhanced. Other tumors were notaffected (73). The lipotrope-deficient diets have been demonstrated to reduce the activity of hepatic metabolizingenzymes, such as aminopyrene demethylase, p-nitroanilinedemethylase, and B(a)P hydroxylase (72), and also toincrease the mitotic rate in the liver (71).

Lipids

Both the amount and nature of the lipid component of thediet may vary. The high caloric value of fat makes itessential to feed equicalonic amounts of each diet. An earlyexperiment in which tumors were produced by skin paintingwith B(a)P, MCA, or dibenz(a,h)anthracene showed that, inthe case of each of 5 different fats, 3 different basal rations,and 2 strains of mice, the tumor incidence increased whenthe dietary level of fat exceeded 15% (35). The result couldhave been due to the fat content of the diet, or to theresultant higher energy content that led to increased bodyweight. Tannenbaum (96, 98) and Silverstone and Tannenbaum (86, 88) showed by using equicaloric diets that aregimen that contained enhanced levels of fat increased the

Table 2The efftct of 10, 20, and 51% casein on longevity, spontaneous tumor incidence. and number of bladder papillomas in rats°

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Nutrition and Experimental Carcinogenesis

incidence of B(a)P-induced skin tumors in Swiss, C57Black, and DBA mice, and of naturally occurring hepatomas in C3H mice. With mammary tumors in DBA mice,either the latency was reduced or the number of tumorsincreased. There was no effect on s.c. sarcoma or lungadenoma induction. The positive effects were of a lowerorder than those seen with caloric restriction, which led tothe suggestion that they may have been due to different“energyvalues― of fat and carbohydrate and that caloricintake is an imprecise parameter in this type of work (7).

The importance of the type of fat in the diet is wellillustrated by the induction of hepatomas in rats fed DAB.Substitution of hydrogenated coconut oil for corn oilreduced the number of hepatomas obtained at 6 months(50), although the more potently carcinogenic 3'-methylderivative did not show the effect (28). The fatty acidsobtained from hydrogenated coconut and corn oils gave riseto similar tumor yields in the experiments involving DAB(38). Other oils used in similar experiments gave variablehepatoma yields (39, 5 1). It has been suggested that thetumor-inhibitory fats enable the liver to store riboflavinmore efficiently and that this leads to the greater activity ofdetoxifying enzymes, for which riboflavin is part of acofactor (52).

Beef fat (35% of diet) enhances the yield of intestinaltumors induced by azoxymethane in rats (60). The bodyweight of rats treated with this compound in normal andbeef fat diets was similar, although those treated with beeffat diets without carcinogen were heavier. The enhancementmay therefore be a direct result ofthis fat supplement, but itis unclear as to whether only beef fat is effective or if otherfats could be substituted. Other aspects of experimentalintestinal cancer have been discussed by Weisburger et a!.(70).

Cycloproprenoid fatty acids may be derived from rawcotton seed oil or Sterculiafoetida oil. These substances actas cocarcinogens in hepatocarcinogenesis by aflatoxin B1 inrats (61, 89). The effect on diethylnitrosamine carcinogenesis in rats was much smaller (61).

Vitamins

Variation in the level of the vitamin B complex in the dietfrom the minimum required to keep the animals healthy to 9times the level did not influence the yield of mammarytumors in DBA mice or of induced skin tumors in C3H orDBA mice (102). Diets low in vitamin B complex had little,if any, inhibitory effect on skin tumor induction in mice (8).Nevertheless, in specific situations, changes in the level ofcertain vitamins may alter the carcinogenic response.

Vitamin A. A deficiency of this vitamin leads to squamous changes in the respiratory and lower urinary tracts(32, 114). The influence of this deficiency on carcinogenesishas not been studied, possibly because of the difficulty inmaintaining the health of the test animals. However, therehas been interest in the apparent protective effect of highlevels of this vitamin since Chu and Malmgren (12) firstindicated that it protected against hydrocarbon-inducedtumors. Feeding 0.5% vitamin A palmitate to hamsters

inhibited formation of dyskeratotic lesions, as well ascarcinomas of the forestomach and small intestine, inducedby DMBA and B(a)P, and against esophageal dyskeratoticlesions induced by the former hydrocarbon. A considerablevolume of evidence on the protective effect of dietary ortopical vitamin A on skin tumor production in mice byhydrocarbons, often in combination with croton oil promotion, has been obtained (4—6, 18, 83). Shamberger (83)showed that topically applied fl-carotene, a vitamin Aprecursor, which is converted to vitamin A in the intestine,enhanced the incidence of papillomas induced by DMBAand croton oil, whereas retinyl acetate and retinol inhibitedpapilloma formation. Retinol also inhibited papillomasinduced by the hydrocarbon and phenol, as a promotingagent. It was shown that lysosomal labilizers, such asfilimarisin, a polyene antibiotic, and vitamin A, had aconsiderable protective effect, whereas the lysosomal stabilizers, chloroquine and hydrocortisone, enhanced the tumoryield. The inhibitory effect of vitamin A on carcinogenesiswas suggested to be due to the destabilization of thelysosomes of “premalignant―cells.

Schmählet a!. (81) failed to demonstrate any protectiveeffect of vitamin A (palmitate and acid) on the induction oftumors by painting B(a)P on mouse skin. This experimentand another on injection site fibrosarcomas induced by thesame chemical may be criticized, because the short latencyof the induced tumors indicates that a massive carcinogenicstimulus was used, and that may have overridden anyprotective effect of vitamin A. In the hamster cheek pouch,topical application of DMBA and vitamin A was shown toinduce more tumors per animal and a greater volume oftumor tissue than the hydrocarbon alone (43). The numberof animals used was small.

The effect of vitamin A derivatives on bronchial carcinogenesis is confused. Original observations indicated thatdietary retinyl palmitate inhibited induction of lower respiratory tract tumors by B(a)P and ferric oxide dust in thehamster (77), but a recent experiment has produced anenhancement rather than an inhibition (90). An inhibition inlung tumor incidence followed feeding high levels of ret inylacetate to rats given 2 intratracheal instillations of MCA(15). The appearance of squamous cell carcinomas wasincreased in lung tissue fragments treated with MCA andimplanted i.m. into syngeneic BALB/c mice (91). A failureto protect against carcinogenesis has been observed forvitamin A in the induction of neurogenic tumors bynitrosomethylurea and of squamous cell carcinomas of thebladder epithelium and liver tumors by dibutylnitrosamine(81).

The utility of vitamin A as an anticarcinogenic treatmentis problematical in view of those experiments producingenhancement. Besides the lysosomal labilization reportedby Shamberger (83), Hill and Shih (33) have shown that 14vitamin A derivatives inhibited the metabolic activation ofB(a)P and other polycyclic aromatic hydrocarbons by livermicrosomes. The extent of inhibition varied with thederivative. It is clear that only further critical experimentation can clarify the present confusion.

Thiamine (Vitamin B1). This vitamin is destroyed by

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D. B. Clayson

thiamase present in bracken fern. When rats were fed driedbracken fern (33% of the diet), all the animals developedintestinal tumors, and 2 of 22 developed bladder tumors.When a supplement of thiamine (2 mg weekly) wasprovided, the intestinal tumor incidence was unaffected,whereas bladder tumors were induced in more than 50% ofthe rats. There were no differences in average daily foodintake up to 6 months and no significant differences insurvival rates (65).

Riboflavin (Vitamin B2). Riboflavin inhibited formationof hepatic tumors induced by DAB (36). It is an essentialconstituent of certain cofactors of detoxifying enzymes (52)and is considerably less effective against the 3'-methyl derivative. Riboflavin analogs (7-ethyl-8-methyl- and 8-ethyl7-methyl- l0(D-ribityl)-iso-alloxazine) are more effectivethan the parent compound against 3'-methyl-4-dimethylaminoazobenzene and 3'-methyl-4'-ethyl-4-dimethylaminoazobenzene (41).

Pyridoxine (Vitamin B6). A deficiency of pyridoxineprotects the rat liver from injury by FAA and permits theanimals to survive longer and thus to develop bladdertumors (48). The pyridoxine deficiency may influencetryptophan metabolism (see above).

Ascorbic Acid (Vitamin C . Because of its ability toinhibit hyaluronidase, ascorbic acid may strengthen theground substance of the tissues. This has been postulated toinhibit cell proliferation and led to the suggestion that a veryhigh intake of ascorbic acid may aid in cancer prophylaxis(10). This idea requires confirmation.

Ascorbic acid reduces sodium nitrite to nitrogen oxides.It thus inhibits the in vivo and in vitro nitrosation ofsecondary and tertiary amines, amides, and ureas to formpotently carcinogenic nitrosamines and nitrosamides(53—55).This action of ascorbic acid assumes considerableimportance in light of the use of nitrite as a food preservative and because certain drugs may be readily nitrosated (26,44). Some foods, e.g., milk, have been shown to retard thenitrosation reaction (23).

Inorganic Constituents

When the proportion ofa balanced mineral supplement inthe diet was altered, the incidence of naturally occurringmammary tumors and hepatomas, or of induced skintumors in DBA mice was not affected, provided isocaloricdiets were used (103). Nevertheless, specific alterations inthe levels of certain constituents of the mineral mixture mayhave a profound effect on carcinogenesis.

Iodine. Iodine deficiency, or the administration of goitrogens, may lead to thyroid tumors. In the presence of acarcinogen such as FAA (3), or of thyroid irradiation (19),high yields of malignant thyroid tumors may be obtained.Goitrogens or iodine deficiency lead to a lowering of thyroidhormone levels in blood with a consequent homeostaticincrease in the levels of thyroid-stimulating hormone. This,if continuous, results in thyroid adenomas and, with acarcinogenic stimulus, in thyroid cancers.

Copper Salts. In excess, copper salts have been shown todelay azo dye hepatocarcinogenesis. The earlier observa

tions (34, 37, 66, 84) are suspect, as the body weight of therats was not recorded. Liver tumors induced by 3-methoxy-4-aminoazobenzene and its N-methyl derivativewere inhibited by the incorporation of 0.5% cupric oxyacetate in the diet. The excess copper did not, however, affectthe incidence of ear duct tumors. The rats in the differentgroups consumed equivalent amounts of food (24). In afurther small experiment, it was shown that the same levelof cupric oxyacetate did not affect induction of skin tumorsby painting 3-methoxy-DAB (25). In diets containing eitherI ppm copper (deficient) or 800 ppm copper (excess), littledifference was found in the induction of liver tumors byFAA, although the incidence of tumors of other sites wasdiminished ( 11). An earlier experiment failed to show thatcopper affected 2-fluorenylamine carcinogenesis (29).DMN-induced kidney neoplasms were frequent on a copper-deficient diet but were absent on an excess copper-contaming diet ( 11). However, the latter induced toxicity andreduction in body weight, and thus interpretation of theseobservations is difficult. There is a need for further criticalobservations in this area.

Selenium. An essential trace element, selenium, on feeding at toxic levels, has given rise to hepatomas (57). Thesemay be a consequence of cirrhosis due to levels of 5, 7, or 10ppm ammonium potassium selenide or, possibly, because ofa chance carcinogenic contaminant in the diet. An attemptto repeat this observation cannot be considered adequate,because of the failure to report on controls (105).

Selenium is a powerful antioxidant and may therefore beexpected to inhibit carcinogenesis (see below). Clayton andBaumann (14) reported a reduced liver tumor incidence at20 weeks when 3'-methyl-4-dimethylaminoazobenzene wasfed to rats for the 1st and 3rd 4-week period of theexperiment, and when a diet containing 5 ppm seleniuminstead of the basal diet was fed in the 2nd 4-week-period.This effect was confirmed and body weight data were given.Shamberger (82), using sodium selenide or selenate, showedthat selenium supplementation had, at best, a weak andinconsistent effect on polycyclic aromatic hydrocarboninduced cutaneous cancer in mice. No significant effectswere obtained with MCA painting; the use of DMBA andcroton oil or croton resin gave variable results while, withB(a)P, fewer tumors were obtained. With FAA, higherlevels of selenium (2.50 and 0.50 ppm) apparently protectedagainst tumors as compared with rats given toxic seleniumdeficient diets (0. 10 and 0.00 ppm) (3 1). Body weightsunfortunately were not discussed, and therefore the significance of this observation is in doubt. The effect of dietaryselenium is obscure.

Enzyme Inducers and Antioxidants

The alteration in the relative levels of metabolizingenzymes, known as induction, may be brought about by awide variety of substances, including certain polycyclicaromatic hydrocarbons, quinones, chlorocarbons, and barbiturates. These substances, whether carcinogens or not,may profoundly influence carcinogenesis induced by another agent (1, 16, 49), but will not be discussed here as they

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betweenthesediets°ModerateTumorsbSevereor

severe%Tumor(allglomerulomyocardialproteinbearers°types)nephritisfibrosisProstatitis1026294<1522293818410512839391812Choice6291563862

Nutrition and Experimental Carcinogenesis

are the subject of another paper in the symposium (112).The antioxidants provide a similar group of chemicals

whose effects in the diet have been extensively investigated.The number of lung adenomas induced in female strain Amice by either diethylnitrosamine or 4-nitroquinoline I-oxide was significantly reduced by feeding BHA or ethoxyquin (108). BHA and BHT inhibited the formation ofDMBA-induced forestomach tumors in female HA/ICRmice, mammary tumors in female Sprague-Dawley rats,and adrenal necrosis and general toxicity in rats (109). Infurther studies on strain A mice, BHA was given from 3weeks before treatment with the carcinogen to the end of theexperiment. The number of lung tumors/mouse induced byB(a)P, DMBA, urethan, and uracil mustard was reduced.On feeding dibenz(a,h)anthracene, DM BA, or 7-hydroxymethyl-12-methylbenz(a)anthracene in diet, fewer lungtumor-bearing animals and fewer tumors/mouse werefound in the presence of BHA (110). FAA carcinogenesiswas likewise inhibited by BHT, but not by a different type ofantioxidant, p-phenylenediamine (106), and BHT delayedthe appearance of rat liver tumors induced by DAB andreduced the level of protein-binding (27). These antioxidantsprovide one of the more consistent and hopeful examples ofcarinogenesis inhibition. Their mode ofaction remains to beelucidated, but Wattenberg (1 11) has postulated that BHAand BHT may act partly through an enzyme-inductive effectand partly through their antioxidant properties.

Discussion

This review emphasizes the extent to which changes innutrition may affect the incidence of tumors induced byeven the most potent carcinogens. The overriding factor isthe dependence of the yield of many tumor types on thecaloric value of the diet or on body weight. Although thisfact has been established for many years, it is apparent thatsome investigators have not realized its significance indetermining the influence of other dietary changes on cancerformation. The other important factor in the study of theeffect ofdiet on chemical carcinogenesis is to avoid too higha level of carcinogen, which may obscure more subtlechanges induced by certain dietary modifications.

Under appropriate conditions, changes in the nutritionalstate of test animals may considerably alter the incidence oftumors. If the same is true for man, it is pertinent to inquirewhether some tumors which appear to be influenced byenvironmental factors are dependent on the nutritionalstatus of the population, rather than on exposure totissue-specific carcinogens. For example, stomach cancer inthe United Kingdom is more prevalent among the lowerincome groups.

Certain aspects of nutrition and experimental cancerrequire further study. The effect of cooking food has beenlargely ignored, with the exception ofthe possible formationof carcinogens in heated fat (63). Also, some individuals,from an early age, have a choice in the type, as well as thequantity, of food which they consume. An experimentdesigned to study this (76) consisted of feeding CharlesRiver COBS rats on 1 of 4 regimens. Three groups received

Table 3A comparisonoftumor incidenceandotherdiseasesper UXICharlesRiverCOBS rats fed diets containing 10. 22, or 51% casein or given a choice

a From Ref. 76.

b For 100 rats.

10, 22, or 51% casein in the diet; the other was offered achoice of these diets in separate feeding pots. The rats in thelatter group each consumed different proportions of the 3diets. This group developed significantly more benign, butnot malignant, tumors, severe glomerulonephrosis, severemyocardiofibrosis, and prostatitis, than those rats thatreceived one of the other diets (Table 3). The significantexcess of lesions was reported to remain even after correction for latency, age-specific morbidity rates, populationsize, and length of life. Although the rats given a free choiceof diet had an elevated body weight, this was not enough toexplain the differences. The significance of these results is,as yet, unclear. Nevertheless, if the actual choice of diet,even on a genetically determined basis, influences tumorincidence, this has considerable importance in the humansituation.

The most clearly understood effects of alteration innutrition in experimental carcinogenesis are on the metabolic activation of chemical carcinogens. In order to permitconclusions from animal experiments to be applied to man,there is a necessity for the effects of diet on other facets ofthe carcinogenic process to be elucidated.

References

I. Arcos, J. C., Conney, A. H., and Buu-Hoi, N. G. Induction ofMicrosomal Enzyme Synthesis by Polycyclic Aromatic Hydrocarbonsof Different Molecular Sizes.J. Biol. Chem., 236: 1291-1296,1961.

2. Berg, J., Howell, M., and Silverman, S. Dietary Hypotheses andDiet-Related Researchin the Etiology of Colon Cancer.Health Serv.Rept., 88:915-924, 1973.

3. Bielschowsky,F. Tumours of the Thyroid Produced by 2-Acetylaminofluoreneand Allyl-thiourea. Brit. J. Exptl. Pathol., 25: 90-94,1944.

4. Bollag, W. EffectsofVitamin A Acid (NSC-122758)in Transplantable and Chemically InducedTumors. Cancer ChemotherapyRept.,55:53-58,1971.

5. Bollag, W. Prophylaxis of Chemically Induced Papillomas andCarcinomas of Mouse Skin by Vitamin A-Acid. Experientia, 28:1219-1220,1972.

6. Bollag, W. H. Prophylaxis of Chemically Induced Benign andMalignant Epithelial Neoplasmsby Vitamin A Acid (Retinoic Acid).EuropeanJ. Cancer,8: 689-693, 1972.

7. Boutwell, R. K., Brush, M. K., and Rusch, H. P. The Stimulating

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