Dietary Inhibition of Cancer - ACS Symposium Series (ACS Publications)

Chapter 7

Dietary Inhibition of Cancer

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Diane F. Birt Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 42nd Street and Dewey Avenue, Omaha, NE 68105-1065

There is little data on the inhibition of pesticide carcinogenicity by diet; however, it is anticipated that some of the mechanisms which will be identified for the interactions between nutrition and other dietary components will also apply to the interaction between dietary components and pesticides. Both nutrient and non-nutrient dietary factors have been found to modify chemical carcinogenesis. Nutrients generally act to alter the process of carcinogenesis and do not function as initiators or promoters of cancer. Current research on macronutrients is assess ing the interactions between dietary fat, calories and fiber in cancer induction and promotion. The most promising leads for micronutrient inhibition of cancer are with vitamins A, C and Ε and with selenium. Non -nutrient dietary factors are of particular interest because of negative associations between certain fruit and vegetable consumption and cancer rates. Examples of such factors include some flavonoids and terpenes. This paper will provide examples of how dietary components may function in the inhibition of cancer. Dietary factors have been investigated for their involvement in cancer etiology ever since the importance of environmental factors in cancer became apparent. However, an understanding of the in volvement of dietary factors in the cancer process has developed very slowly. A prime reason for this slow progress is probably the elusive nature of the influence of diet in cancer etiology. For example, in comparison with the association between cigarette smok ing and cancer, the association between diet and cancer is very weak. In considering different sites of cancer, dietary components often have conflicting effects, whereas smoking is associated with an increased rate of cancer at every site where it has an influence. However, diet is probably one of the most important means whereby nonsmokers can control their cancer risk. 0097-6156/89/0414-0107$06.00/0 ©1989 American Chemical Society Ragsdale and Menzer; Carcinogenicity and Pesticides ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

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CARCINOGENICITY AND PESTICIDES

It i s c e r t a i n l y reasonable to assume that dietary factors which have been studied for their a b i l i t y to prevent chemically-induced cancer may be useful i n the prevention of cancer induced by p e s t i cides; however, I could not find recent studies which have explored the relationship between dietary factors and cancer induced by pesticides. The absence of this important data i n the l i t e r a t u r e i s probably due to the decision on the part of investigators studying the relationship of diet and cancer to use well-established, w e l l defined models of chemical carcinogenesis for their dietary studies. I anticipate that diet w i l l be used to modulate pesticide carcinogenesis as our understanding of pesticides and their relationship to cancer expands. Furthermore, I am not aware of pesticides being studied as potential dietary i n h i b i t o r s of cancer, although, as pointed out i n the presentation by Dr. Gary Williams, pesticides such as DDT can influence the metabolism of certain carcinogens i n a manner which would reduce the carcinogenicity of these agents. This chapter w i l l provide an overview of the factors which have been studied most extensively as potential i n h i b i t o r s of cancer. It w i l l stress data in the areas where recommendations have been made to the public ( 1 , 2 ) . We w i l l begin with a discussion of the macronutrients which have received the greatest attention for their pot e n t i a l for modifying cancer r i s k , dietary fat and f i b e r , and the r e l a t i o n of these nutrients to c a l o r i e intake. I w i l l then describe data suggesting that micronutrients such as vitamins A, C, and E , and the trace element selenium, may have some potential i n the i n h i b i t i o n of cancer. F i n a l l y , I w i l l present some recent data i n support of cancer prevention by some non-nutrient components of f r u i t s and vegetables. Dietary F a t , Fiber and Calories High fat diets are generally associated with an increased r i s k of cancer i n people consuming such diets and an enhancement of carcinogenesis i n animals fed such d i e t s . The converse of this should also c e r t a i n l y be considered, a reduction in cancer r i s k i n people consuming low fat diets and an i n h i b i t i o n of cancer i n animals fed low fat d i e t s . In the massive compilation of data prepared by the National Research Council (NRC) on D i e t , N u t r i t i o n and Cancer (J_), the number of studies showing a relationship between dietary fat and cancer was more impressive than the relationship between diet and any other nutrient. "The committee concluded that of a l l the d i e tary components i t studied, the combined epidemiological and experimental evidence i s most suggestive for a causal relationship between fat intake and the occurrence of cancer". People consuming low fat diets have been found to have lower rates of colon, breast, pancreas, and prostate cancer ( 1 , 2 ) . Animals consuming low fat diets generally had reduced rates of cancers induced in the breast, colon, l i v e r , pancreas, lung and skin as shown i n Table I [previously reviewed by B i r t , ( 3 ) ] . This i s p a r t i c u l a r l y true with diets containing fats high i n W-6 fatty acids. Recent work indicates possible i n h i b i t i o n of cancer by W-3 fatty a c i d s . The primary d i f f i c u l t y i n interpreting the studies of the effects of dietary fat on carcinogenesis is the problem of separating the effects of fat from the effects of c a l o r i e s . Diets

Ragsdale and Menzer; Carcinogenicity and Pesticides ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

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109


Table I .

Summary of t h e E f f e c t s o f D i e t a r y F a t on Turaorigenesis

Site

Animal

Agent

Skin

Mouse

Lung

Mouse Hamster

Mammary gland

Rat Mice Rat Rat Rat Rat

None (spontaneous) P o l y c y c l i c hydrocarbon UV l i g h t None Benzo(a)pyrene (BP) on f e r r i c o x i d e N - n i t r o s o b i s ( 2 - o x o p r o p y l ) a m i n e (BOP) 7,12-dimethylbenz(a)anthracene Spontaneous A c e t y l a m i n o f l u o r e n e (AAF) M e t h y l n i t r o s o u r e a (MNU) X-irradiation 1 , 2 - d i m e t h y l h y d r a z i n e (DMH) Azoxymethane (AOM) methylazoxymethanol a c e t a t e (MAM) 3,2'-diraethyl-A-amino-biphenyl (DMAB) MNU None Aminoazo dyes A f l a t o x i n Β (AFB) AAF BOP BOP A z a s e r i n e (AZA) None (promoted w i t h t e s t o s t e r o n e ) None DMH DMH BOP

Colon

Liver

Mouse Rat Hamster

Pancreas

Hamster Rat Rat Mouse Rat Rat Hamster

Prostate Brain Ear duct Kidney

NE = no e f f e c t .

E f f e c t of high^fat diet

Adapted from r e f e r e n c e 3.


+ + + ,NE

+ + ,NE + t,NE +

+

NE Ε +

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CARCINOGENICITY AND

PESTICIDES

e n r i c h e d i n f a t have an e l e v a t e d c a l o r i c d e n s i t y . Thus, animals consuming these d i e t s may consume e x t r a c a l o r i e s , or they may u t i l i z e the c a l o r i e s consumed i n a more e f f i c i e n t manner. T h i s i s i m p o r t a n t i n u n d e r s t a n d i n g the i n f l u e n c e of c a l o r i e s on cancer because i t i s w e l l known t h a t reduced c a l o r i e i n t a k e can a l s o i n h i b i t c a r c i n o g e n e s i s (3) and c a l o r i e i n t a k e appears t o be a f a c t o r i n human b r e a s t and c o l o n cancer ( 4 , 5 ) . S t u d i e s u s i n g the r a t mammary c a r c i n o g e n e s i s system i n d i c a t e d t h a t r e s t r i c t i o n of a h i g h f a t d i e t t o the l e v e l of energy consumption by the low f a t c o n t r o l r e s u l t e d i n c o n s i d e r a b l e i n h i b i t i o n of t u m o r i g e n e s i s , s u g g e s t i n g t h a t some o f the i n f l u e n c e of d i e t a r y f a t on mammary t u m o r i g e n e s i s may be due to the i n f l u e n c e of c a l o r i e s ( 6 ) . However, r e c e n t i n v e s t i g a t i o n s i n my l a b o r a t o r y demonstrated t h a t p a n c r e a t i c c a r c i n o g e n e s i s was enhanced i n hamsters f e d a h i g h f a t d i e t i r r e s p e c t i v e of whether d i e t s were f e d at c o n s t a n t and s l i g h t l y r e s t r i c t e d c a l o r i c amounts or i n an ad l i b i t u m manner where e x c e s s i v e c a l o r i e s were consumed by the h i g h f a t group (_7). D i e t a r y f i b e r ' s e f f e c t s on c a r c i n o g e n e s i s have been the t o p i c of much debate ( 8 ) . The p u b l i c w i d e l y b e l i e v e s t h a t the consumption of f i b e r r e s u l t s i n reduced r i s k of c o l o n c a n c e r , yet d a t a from case c o n t r o l s t u d i e s w i t h humans i n d i c a t e s t h a t f i b e r consumption i s not s t r o n g l y a s s o c i a t e d w i t h reduced r i s k of c o l o n c a n c e r , and some s t u d i e s have even shown an i n c r e a s e d r i s k a s s o c i a t e d w i t h h i g h f i b e r i n t a k e s (9)· F u r t h e r m o r e , d a t a from s t u d i e s w i t h animals suggest t h a t f i b e r can i n h i b i t , enhance o r have no i n f l u e n c e on c o l o n c a r c i n o g e n e s i s , depending upon the form of f i b e r g i v e n , when i t i s g i v e n r e l a t i v e t o the c a r c i n o g e n , and the type of d i e t i n w h i c h i t i s g i v e n (8). V i t a m i n and M i n e r a l I n h i b i t i o n of Cancer V i t a m i n A has been one of the most e x t e n s i v e l y s t u d i e d m i c r o n u t r i e n t s f o r the p r e v e n t i o n of cancer ( 1 0 ) . The n u t r i t i o n a l r o l e of v i t a m i n A i n c l u d e s r e g u l a t i o n of normal d i f f e r e n t i a t i o n . Cancer e p i d e m i o l o g y suggested t h a t the consumption of foods r i c h i n v i t a m i n A may be a s s o c i a t e d w i t h a reduced r a t e of a number of forms o f cancer, i n c l u d i n g lung (11-14). Such r e s u l t s f u r t h e r suggest t h a t v i t a m i n A or i t s p r e c u r s o r s may be p a r t i c u l a r l y b e n e f i c i a l i n the p r e v e n t i o n of l u n g cancer i n smokers ( 5 8 ) . A n i m a l i n v e s t i g a t i o n s have used a number of analogues of v i t a m i n A w h i c h possess reduced t o x i c i t y and were a n t i c i p a t e d to p r o v i d e i n c r e a s e d p r o t e c t i o n a g a i n s t cancer as w e l l as u s i n g v i t a m i n A i t s e l f . A summary of s t u d i e s w i t h v i t a m i n A d e f i c i e n c y i n c r e a s i n g cancer i n d u c t i o n and s u p p l e m e n t a t i o n w i t h v i t a m i n A o r i t s analogues ( r e t i n o i d s ) i n h i b i t i n g cancer i n d u c t i o n was r e c e n t l y p u b l i s h e d (10) , and the o v e r a l l e f f e c t s are shown i n T a b l e I I . I n g e n e r a l , v i t a m i n A and analogues of v i t a m i n A were p a r t i c u l a r l y e f f e c t i v e i n p r e v e n t i n g u r i n a r y b l a d d e r t u m o r i g e n e s i s i n a model u s i n g a n i t r o s a m i n e c a r cinogen ( 1 5 ) , but not i n a n o t h e r model u s i n g a n i t r o f u r a n ( 1 6 ) . Mammary g l a n d c a r c i n o g e n e s i s i n r a t s was i n h i b i t e d by v i t a m i n A and i t s analogues ( 17), but mammary t u m o r i g e n e s i s i n mice was not i n f l u enced ( 1 8 ) . I n g e n e r a l , r e t i n o i d s have shown v a r i a b l e e f f e c t s on t u m o r i g e n e s i s i n the s k i n , l u n g , l i v e r , c o l o n , and pancreas ( 1 0 ) . More r e c e n t s t u d i e s w i t h r e t i n o i d s have a s s e s s e d the p o t e n t i a l of


7. BIRT


Table I I .

Summary of the Influence ç f Retinoids on Chemical Carcinogenesis 3

2

Effect

Site

Species

Agent

Retinoid treatment

Skin

Mice Mice Mice

DMBA DMBA + TPA UV l i g h t

V i t . A analogues Retinoic acid Retinoic Ac

Ψ

Salivary glands

Hamsters

DMBA DMBA

V i t . A def. 13 c i s r e t . Ac

NE Ψ

Mammary gland

Rats Rats Mice Mice

DMBA MNU DMBA None

Ret. acetate Ret. acetate + analogues analogues Retinyl acetate

Ψ Ψ NE NE

Forestomach

Hamsters Hamsters

DMBA BP

V i t . A palmitate V i t . A palmitate

Ψ Ψ

Urinary bladder

Rats Mice Rats Rats Rats

BBN BBN MNU FANFT FANFT

V i t . A analogues V i t . A + analogues 13 c i s r e t . Ac. V i t . A def. Ret. palmitate

Ψ Ψ Ψ

Rats Rats Hamsters

3MC 3MC BP-Fe0

V i t . A def. Ret. acetate Retinyl acetate

Trachea

Hamsters

MNU

Vit.

A analogues

Liver

Rats Rats Hamsters Rats

AFB DMAB BOP AZA

Vit. Ret. Vit. Vit.

A def. acid A analogues A analogues

Colon

Rats Rats Rats Rats

AFB MNNG DMH MNU

Vit. A Vit. A 13 c i s Vit. A

Pancreas

Hamsters Rats

BOP AZA

Vit. Vit.

Lung

3

3

+

NE \

NE

Ψ +

+ ΝΕ

def. def. r e t . Ac analogues

t NE Ψ Ψ \ NE

A analogues A analogues

f NE Ψ

References were published previously by B i r t (10). Abbreviations are as i n Table I and: DMBA « 7,12-dimethylbenzanthracene; TPA = 12-0-tetradecanoylphorbol-13-acetate; BBN = butyl(4-hydroxy)butyl-nitrosamine; FANFT = N - [ 4 - ( 5 - n i t r o - 2 - f u r y l ) - 2 t h i a z o l y l ] formamide; 3MC = 3-methylcholanthrene; MNNG - N-methylN'-nitro-N-nitrosoguanidine. Def. = deficiency; r e t . Ac. » r e t i n o i c acid; NE » negative.


112

CARCINOGENICITY AND

PESTICIDES

combining r e t i n o i d s w i t h o t h e r d i e t a r y agents such as s e l e n i u m , v i t a m i n E, or v i t a m i n C w h i c h may prevent c a n c e r . Such s t u d i e s have had mixed r e s u l t s . For example, s t u d i e s by Ip i n d i c a t e d a p o t e n t i a t i o n of the i n h i b i t i o n of cancer i n r a t s t r e a t e d w i t h s e l e n i u m and v i t a m i n A f o l l o w i n g c a r c i n o g e n t r e a t m e n t ( 1 9 ) , but r e s u l t s from our l a b o r a t o r y i n d i c a t e d an i n h i b i t i o n of s k i n t u m o r i g e n e s i s i n mice g i v e n the r e t i n o i d 4 - h y d r o x y - r e t i n a m i d e but an a b l a t i o n of t h i s e f f e c t when s e l e n i u m or s e l e n i u m and v i t a m i n Ε were added to the d i e t ( P e l l i n g e t a l . , u n p u b l i s h e d o b s e r v a t i o n ) . A s c o r b i c a c i d has l o n g been known t o p r e v e n t n i t r o s a t i o n ( 2 0 ) . I t i s q u i t e p o s s i b l e t h a t d i e t a r y a s c o r b i c a c i d i s important i n p r e v e n t i n g human c a n c e r which i s caused by endogenous n i t r o s a m i n e f o r m a t i o n ( 2 1 ) . There i s e v i d e n c e , f o r example, t h a t g a s t r i c cancer r i s k , w h i c h i s a form of cancer l i k e l y to be caused by endogenous n i t r o s a m i n e f o r m a t i o n under some c o n d i t i o n s , i s lower i n areas where the consumption of f r e s h f r u i t s and v e g e t a b l e s i s h i g h ( 2 1 ) . A n i m a l i n v e s t i g a t i o n s c l e a r l y demonstrated t h a t n i t r o s a m i n e f o r m a t i o n from n i t r i t e and m o r p h o l i n e was reduced i n the presence of a s c o r b i c a c i d and f u r t h e r t h a t cancer i n d u c e d by g i v i n g n i t r i t e and m o r p h o l i n e was i n h i b i t e d i n animals given a s c o r b i c a c i d (21). In a d d i t i o n , ascor b i c a c i d has been shown t o i n h i b i t cancer i n d u c e d by a number of preformed c a r c i n o g e n s as reviewed p r e v i o u s l y (10) and shown i n T a b l e III. A l p h a - t o c o p h e r o l has been shown t o be u s e f u l i n the p r e v e n t i o n of n i t r o s a t i o n i n non-aqueous systems (20,22). A d d i t i o n a l l y , car c i n o g e n e s i s by preformed c a r c i n o g e n s has been i n h i b i t e d by a l p h a t o c o p h e r o l , as i s shown i n T a b l e IV. I n t e r e s t i n g l y , 7 , 1 2 - d i m e t h y l b e n z ( a ) a n t h r a c e n e (DMBA)-induced c a r c i n o g e n e s i s i n the mammary g l a n d was i n h i b i t e d o n l y i n r a t s f e d h i g h f a t o r h i g h s e l e n i u m l e v e l s w i t h the v i t a m i n Ε supplement (23,24). Selenium has been e x t e n s i v e l y s t u d i e d f o r i t s a b i l i t y to i n h i b i t c a r c i n o g e n e s i s ( T a b l e V ) . E p i d e m i o l o g i c a l s t u d i e s have suggested t h a t e l e v a t e d s e l e n i u m i n the blood was a s s o c i a t e d w i t h a r e d u c t i o n i n cancer r a t e s at a number of s i t e s ( 2 5 ) . I n v e s t i g a t i o n s u s i n g a n i m a l models have demonstrated a c o n s i s t e n t i n h i b i t i o n of mammary and c o l o n c a r c i n o g e n e s i s i n r a t s , but enhancement of c a r c i n o g e n e s i s was r e p o r t e d i n the pancreas and s k i n of a n i m a l s f e d h i g h s e l e n i u m d i e t s and t r e a t e d w i t h c h e m i c a l c a r c i n o g e n s (10,26). P a n c r e a t i c c a r c i n o g e n e s i s of d u c t u l a r morphology, s i m i l a r to the most common forms of the human d i s e a s e , was e l e v a t e d o n l y under s p e c i f i c c o n d i t i o n s , whereas p a n c r e a t i c a c i n a r c e l l nodules were i n h i b i t e d ( 2 6 , 2 7 ) , s u g g e s t i n g p o s s i b l e i n h i b i t i o n of a c i n a r p a n c r e a t i c tumorigenesis. U s i n g the two-stage model of s k i n t u m o r i g e n e s i s , we found an enhancement of s k i n tumor promotion i n mice f e d d i e t a r y s e l e n i u m supplements f o l l o w i n g a h i g h dose of c a r c i n o g e n . W i t h lower doses of c a r c i n o g e n no i n f l u e n c e was observed ( P e l l i n g et a l . , unpublished data). N o n - N u t r i e n t , I n h i b i t o r s of Cancer from F r u i t s and

Vegetables

The consumption of f r u i t s and v e g e t a b l e s has been a s s o c i a t e d w i t h a r e d u c t i o n i n cancer r a t e at a number of s i t e s . S t u d i e s have r e p o r t ed reduced r a t e s of g a s t r i c , c o l o n and r e c t a l , b l a d d e r , p r o s t a t e and b r e a s t c a n c e r r a t e s i n a s s o c i a t i o n w i t h c r u c i f e r o u s v e g e t a b l e s as


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113

Dietary inhibition of Cancer

Table I I I .

Summary of the Influence ç f Vitamin C on Chemical Carcinogenesis

Site

Species

Agent^

Vitamin C route (dosage)

Skin

Mouse Guinea pig Guinea pig

UV 3MC 3MC

Diet (100 g/kg) Varied ip

Ψ NE

Nose

Hamster

DEN + cigarette

smoke

Diet (10 g/kg)

Ψ

Trachea

Hamster

DEN + cigarette

smoke

Diet (10 g/kg)

Ψ

Lung

Mouse

DMN

Diet (23 g/kg)

Ψ

Mammary

Rat

DMBA

Water (2.5 g/kg)

NE

Colon

Rat Rat Mouse Rat

DMH DMH DMH MNU

Diet Diet Diet Diet

Ψ

Rat Hamster Hamster

DMH estradiol DES

Diet (2-10 g/kg)

Ψ Ψ Ψ

BBN

Diet (50 g/kg) Ascorbic acid Diet (50 g/kg) Sodium ascorbate Diet (50 g/kg) Sodium ascorbate

NE

Kidney

Urinary Rat bladder

BBN MNU

Effects

(2.5-10 g/kg) (50 g/kg) ( L Y

DMBA

Diet (50 mg/kg)

(high fat) NE (low Se) *L Y

DMBA

Diet (2

g/kg)

2References were published previously by B i r t Abbreviations are as i n previous tables and: dibenzpyrene.

(high Se) NE

(10). DBP - 3,4,9,10-


BIRT


T a b l e V·

Summary o f t h e I n f l u e n c e o| Selenium on C h e m i c a l C a r c i n o g e n e s i s Effect

Site

Species

Agent^

Skin

Mice Mice Mice Mice

uv l i g h t 3MC a-Pyrene DMBA + TPA

Rat Rat Rat

DMAB AAF AFB

Ψ

Trachea

Hamster

MNU

NE

Lung

Rat

BOP

Ψ

Mammary g l a n d

Mice Rat Rat

DMBA DMBA MNU

Ψ Ψ Ψ

Colon

Rat Rat Rat

DMBA BOP AOM

Ψ Ψ Ψ

Pancreas

Hamster

BOP

+

Liver

Ψ 4Ψ +

R e f e r e n c e s were p u b l i s h e d p r e v i o u s l y by B i r t ( 1 0 ) · A b b r e v i a t i o n s a r e as i n p r e v i o u s t a b l e s .


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reviewed previously (28). A recent case control study i n China found an elevated rate of stomach cancer among people consuming less Chinese cabbage ( 2 9 ) · Animal experiments i n which dried cruciferous vegetables are incorporated into diets have provided mixed support for the potential of these vegetables i n cancer prevention (reviewed in 2 8 ) · Studies of mammary (30) and l i v e r (31) carcinogenesis and lung metastasis (32) indicated an i n h i b i t i o n ; however, studies of skin (33), pancreas (33) and colon (34) cancer found an enhancement of cancer under some experimental conditions. P a r t i c u l a r compounds reported to be present i n or derived from those present i n c r u c i f erous vegetables, have been studied i n recent years for their a b i l i t y to prevent carcinogenesis. Indole-3-carbinol has been extensively studied, and although there i s evidence that this agent may be effective i n i n h i b i t i n g cancer i n i t i a t i o n (35) i t appears that i t has the potential to increase cancer rates i f fed during tumor promotion (36). Other components of cruciferous vegetables, including dithiolthiones (37) and insoluble fibers ( B i r t , unpublished results) are under active investigation. Since studies on p a r t i c u l a r foods indicate varying degrees of benefit i n the prevention of cancer, many investigators i n this area are studying a wide variety of natural dietary components which do not have known roles as essential nutrients but which have been i d e n t i f i e d i n foods as potential i n h i b i t o r s of cancer. In the limited space available here, I w i l l provide an overview of some selected agents and the types of studies being conducted on these compounds· Flavonoids. Flavonoids are ubiquitously distributed in vascular plants. Over 2000 members of the flavonoid class have been described (38). They serve many functions i n the plant, including t h e i r a c t i v i t i e s as potent antioxidants and metal chelators (39). Because of their wide d i s t r i b u t i o n i n plants, they are consumed i n large quantities by people. It i s estimated that we consume at least 1 gram (g) of plant flavonoid d a i l y (40). L i t t l e i s known regarding the b i o l o g i c a l effects of plant flavonoids in mammalian systems. An extensive survey of the mutagenicity of several flavonoids has been conducted and two common plant flavonoids, quercetin and kaempferol, were i d e n t i f i e d as being mutagenic (41). Because of this observation, quercetin, the most mutagenic of the two compounds, has been extensively studied for i t s carcinogenicity (42-47). Only one study has shown any carcinogenicity, and this report i s suspect because other carcinogenic agents were used i n the experiment and the y i e l d of cancer i n the quercetin group was very high (42). More recently, quercetin has been investigated for i t s a b i l i t y to prevent the promotion phase of carcinogenesis. Nishino et a l . (48) t o p i c a l l y applied DMBA to the backs of mice and t e l e o c i d i n , the promoter, was administered twice weekly beginning one week after initiation. Quercetin was applied either 40 minutes before the t e l e o c i d i n or concurrently. Potent i n h i b i t i o n of the tumor i n c i dence and prolongation of the latency period were observed after administration of the flavonoid. For example, after 20 weeks of promotion, an 83% reduction i n the number of papillomas per mouse was observed. In investigations where the flavonoid was adminis-


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tered i n the diet and skin tumorigenesis was investigated, no i n h i b i t i o n was reported (49). However, a recent report on mammary carcinogenesis induced by DMBA showed an i n h i b i t i o n with quercetin administered i n the diet at a 1.0% l e v e l (50). Numerous laboratories have investigated the influence of flavonoids on biochemical events which respond to tumor promoters (51,52). For example, a well known effect of tumor promoters applied to the skin of mice i s the induction of ornithine decar boxylase (ODC). ODC i s the rate l i m i t i n g enzyme i n polyamine synthesis and i t s a c t i v i t y i s elevated by agents which lead to c e l l u l a r p r o l i f e r a t i o n . Several laboratories have investigated the influence of flavonoids applied before or with tumor promoters on the induction of ODC. The promoters cause a substantial increase i n ODC and the flavonoids quercetin, kaempferol, l u t e o l i n , morin, f i s e t i n , apigenin and robinetin (49,53,54) have been shown to i n h i b i t this induction to varying extents. ^ The influence of flavonoids on the incorporation of Ρ into phospholipids, another hallmark of tumor promotion, ha^ also been determined. Quercetin blocked teleocidin-stimulated P-incorporation i n a dose responsive manner (48). F i n a l l y , flavonoids were also effective i n blocking promoter induced protein kinase C (PKC) induction as measured by the phosphorylation of HI histone or the phosphorylation of endogenous proteins ( 5 5 ) · Studies from this laboratory determined the influence of apigenin on tumor promotion by pre-treating mice with apigenin prior to treatment with 12-0-tetradecanoylphorbol-13-acetate (TPA) and preliminary results are shown i n Table VI (Wei e_t a l . , unpublished data). A dose response i n h i b i t i o n was observed i n the incidence, and number of skin tumors and carcinomas were i n h i b i t e d by both doses of apigenin. We have also determined that apigenin treatment i n h i b i t s the TPA-induced phosphorylation of epidermal proteins. Our aim i s to develop a system to improve the uptake of apigenin to body organs and determine the influence of apigenin on tumorigenesis at other s i t e s .

Table V I .

I n h i b i t i o n of TPA-induced Promotion by Apigenin i n SENCAR Mice I n i t i a t e d with DMBA Number of papillomas/ effective mouse

Number of carcinomas/ effective mouse

Apigenin dose (/imole)

Number of effective mice

0

30

93

7.5

53

1.3

5

29

59

2.5

10

0.5

20

28

39

1.8

14

0.3

% Papilloma incidence

% Carcinoma incidence

Unpublished data (Wei, H-C and B i r t , DF). Papilloma data from 29 weeks after DMBA; carcinoma data from 40 weeks after DMBA.



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Terpenes. Another class of compounds which holds considerable promise as i n h i b i t o r s of cancer are the terpenes. D-liraonene, which i s a component of c i t r u s o i l s , i s the terpene which probably has been studied most extensively as an i n h i b i t o r of carcinogenesis. Early studies reported that D-limonene, a mixture of D-limonene with i t s hydroperoxide, and orange o i l were s i m i l a r i n their a b i l i t y to prevent subcutaneous tumors induced by benzo(rst)pentaphene (DBP) (56) but that spontaneous and DBP-induced lung adenomas were reduced i n mice fed D-limonene but not i n those fed orange o i l or the hydro peroxide of limonene. Studies on DMBA-induced mammary carcinogenesis i n SpragueDawley rats indicated that feeding diet containing 1 or 10 g/kg Dlimonene from 1 week before DMBA u n t i l the end of the experiment resulted i n decreased incidence and latency and increased regression of mammary tumors (57). D-limonene was most effective when adminis tered during i n i t i a t i o n , but some i n h i b i t i o n was observed i n rats fed D-limonene during progression (58). A recent report on the Oleanane-type synthetic triterpenoids showed impressive suppression of tumor promotion i n the DMBA-initiated, TPA-promoted model of skin tumorigenesis by t o p i c a l a p p l i c a tion of these compounds (59). For example, application of 81 nmol 18-a and 183~olean-12-ene-3, 323,28-triol i n h i b i t e d the incidence of tumors by 80 and 60%, respectively, f u r t h e r m o r e , these compounds also i n h i b i t e d the incorporation of Ρ into phospholipids of c e l l s cultured with TPA as shown i n Table V I I . These results suggest that these compounds may hold p a r t i c u l a r promise for the prevention of cancer·

Table ^ 1 . Effects of Oleanane-Type Triterpenoids on TPA-Induced Pi incorporation into phospholipids of cultured c e l l s Pi incorporation (% i n h i b i t i o n )

Cells

Triterpenoid

C3HIDT1/2

I83--olean--12--ene-"36 ,23, 28-- t r i o l 18a--olean- •12--ene-- 3 β , 2 3 , 28-- t r i o l

50 80

Swiss 3T3

I83--olean--12--ene--33,23, 28-- t r i o l 18a--olean-•12--ene--33,23, 28-- t r i o l

59 89

SOURCE: Reproduced with permission from ref. 59. Copyright 1988 Cancer Research.

Summary and Conclusions Dietary i n h i b i t i o n of cancer i s being approached through the use of modifications i n macronutrient intakes, micronutrient intakes and the consumption of non-nutrient components of d i e t s . Current recom mendations on dietary prevention of cancer emphasize reduction i n the intake of fat and increased intake of f r u i t s and vegetables. This chapter provides an overview of the type of data being c o l l e c t ed i n support of these recommendations and the approach being taken to further our understanding of this area. In general, dietary


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modification of cancer emphasizes i n h i b i t i o n of the l a t e r stages of the cancer process. It i s assumed that we cannot avoid conditions which w i l l possibly result i n the i n i t i a t i o n events of cancer. These events are caused by such a wide range of agents that i t w i l l probably not be possible to devise a diet which would prevent the i n i t i a t i n g event. Thus, dietary modification w i l l be most useful i n preventing the development of tumors from i n i t i a t e d c e l l s . It i s hoped that the types of dietary modifications being studied w i l l be applicable for the prevention of cancers p o t e n t i a l l y caused by pesticides as well as by other agents.

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