Xenobiotic Metabolism: Nutritional Effects - ACS Publications

14 Influence of Diet on Hormone-Dependent Cancers KENNETH K. CARROLL

Downloaded by TUFTS UNIV on December 11, 2015 | http://pubs.acs.org Publication Date: May 6, 1985 | doi: 10.1021/bk-1985-0277.ch014

Department of Biochemistry, University of Western Ontario, London, Ontario, N6A 5C1 Canada

Evidence that diet affects hormone-dependent cancers comes from epidemiological data and from studies on tumorigenesis in experimental animals. Breast cancer incidence and mortality are positively correlated with the amounts of fat, animal protein and total calories available for consumption in different countries. Of these variables, experiments with animals have provided the strongest support for the correlation with dietary fat. Cancers of the prostate, ovary and uterus also show positive correlations with dietary fat but as yet there is little evidence from animal experiments to support these correlations. Polyunsaturated fats enhance the yield of mammary tumors in animals more effectively than saturated fats, apparently because of a requirement for essential fatty acids, but breast cancer mortality in humans seems to correlate best with the amount rather than the type of dietary fat. Dietary fat appears to act as a promoter rather than an initiator of mammary carcinogenesis in animals. The mechanism is not known but various possibilities are being actively investigated. Promotion of carcinogenesis involves continuing exposure to the promoting agent over a period of time. It is potentially reversible, and experiments with animals have shown that tumorigenesis can be inhibited by reducing the level of dietary fat after a period of promotion with a high-fat diet. Low-fat diets may therefore be useful in prevention and treatment of cancer in humans. My interest in the influence of diet on hormone-dependent cancers was first stimulated about 20 years ago by studies carried out in collaboration with colleagues at the Collip Medical Research Laboratory of the University of Western Ontario. They were involved in studies on the role of hormones in mammary cancer and for this purpose were inducing tumors in rats with 7,12-dimethylbenz(a)anthracene (DMBA) as described by Huggins et al (1). They were concerned to know whether hormonal treatment might affect tumorigenesis by altering the degree and time of exposure of mammary 0097-6156/85/0277-0177$06.00/0 © 1985 American Chemical Society

In Xenobiotic Metabolism: Nutritional Effects; Finley, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1985.

XENOBIOTIC M E T A B O L I S M : NUTRITIONAL EFFECTS

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t i s s u e s t o the DMBA. I n o r d e r t o i n v e s t i g a t e t h i s , I a s s i s t e d them i n d e v e l o p i n g a method f o r a n a l y z i n g DMBA i n t i s s u e s by g a s - l i q u i d chromatography (2) . Much o f my p r e v i o u s r e s e a r c h e x p e r i e n c e had been i n l i p i d b i o c h e m i s t r y and DMBA, a p o l y c y c l i c h y d r o c a r b o n , i s e s s e n t i a l l y a l i p i d x e n o b i o t i c . The s u g g e s t i o n had been made by Dao e t a l (3) t h a t the s p e c i f i c i n d u c t i o n o f mammary tumors by DMBA and o t h e r p o l y c y c l i c hydrocarbons might be due t o t h e i r tendency, as l i p i d s , t o accumulate and p e r s i s t i n the a d i p o s e t i s s u e o f the mammary g l a n d , thereby i n c r e a s i n g the exposure t o the s u s c e p t i b l e mammary e p i t h e l i a l t i s s u e . I f t h i s were indeed a f a c t o r i n the a b i l i t y o f these compounds t o produce mammary tumors, i t seemed t o us t h a t i t might be p o s s i b l e t o i n f l u e n c e t h e i r e f f e c t i v e n e s s by a l t e r i n g f a t metabolism i n the body.


E f f e c t s o f D i e t a r y F a t on Mammary C a r c i n o g e n e s i s One o f the e a s i e s t ways o f a l t e r i n g f a t metabolism i s t o f e e d d i e t s c o n t a i n i n g d i f f e r e n t l e v e l s and types o f d i e t a r y f a t . We t h e r e f o r e c a r r i e d out an experiment i n which w e a n l i n g female Sprague-Dawley r a t s were f e d s e m i p u r i f i e d d i e t s c o n t a i n i n g 0.57 c o r n o i l , 20% coconut o i l o r 207 c o r n o i l . The r a t s were g i v e n a s i n g l e 10 mg i n t r a g a s t r i c dose o f DMBA i n sesame o i l a t 50 days o f age, s i n c e Huggins e t a l (1) had shown t h a t r a t s were most s u s c e p t i b l e a t about t h a t age. Because we wished t o a v o i d any e f f e c t s o f d i e t a r y f a t on a b s o r p t i o n o f the c a r c i n o g e n from the g u t , P u r i n a Chow was s u b s t i t u t e d f o r the s e m i p u r i f i e d d i e t s from two days b e f o r e u n t i l one day a f t e r r e c e i v i n g the DMBA. They were then r e t u r n e d t o the s e m i p u r i f i e d d i e t s and the development o f tumors was f o l l o w e d f o r a p e r i o d o f f o u r months, a t which time t h e animals were a u t o p s i e d . o

o

One o f the advantages o f s t u d y i n g mammary tumors as opposed t o tumors o f i n t e r n a l organs i s t h a t they develop j u s t under the s k i n and c a n be p a l p a t e d as h a r d lumps when they a r e s t i l l v e r y s m a l l . T h i s means t h a t t h e i r development can be f o l l o w e d w i t h o u t k i l l i n g the a n i m a l s . Tumors b e g i n t o appear about a month a f t e r treatment w i t h DMBA, and the numbers c o n t i n u e t o i n c r e a s e w i t h t i m e . They may d e v e l o p i n any o f the s i x p a i r s o f mammary g l a n d s , and animals u s u a l l y develop m u l t i p l e tumors. The r e s u l t s o f our f i r s t experiment showed no s i g n i f i c a n t d i f f e r e n c e s between the groups f e d d i e t s c o n t a i n i n g 0.5% c o r n o i l o r 20% coconut o i l , but i n t h e group f e d the 20% c o r n o i l d i e t , n e a r l y a l l o f the animals developed tumors and t h e r e were about twice as many tumors as i n e i t h e r o f the o t h e r two groups ( F i g u r e 1 ) . The l e v e l s o f DMBA i n the mammary glands a f t e r o r a l a d m i n i s t r a t i o n t o a n i m a l s f e d these d i e t s d i d not show d i f f e r e n c e s t h a t seemed l i k e l y to account f o r the h i g h e r tumor y i e l d i n animals f e d the 20%, c o r n o i l diet (5). Our f i n d i n g t h a t d i e t a r y f a t c o u l d enhance mammary t u m o r i g e n e s i s i n a n i m a l s was n o t i n f a c t a new o b s e r v a t i o n . B e g i n n i n g w i t h the s t u d i e s o f Tannenbaum ( 6 ) , a number o f i n v e s t i g a t o r s had shown t h a t a n i m a l s f e d h i g h - f a t d i e t s develop mammary tumors more r e a d i l y than those f e d l o w - f a t d i e t s . S i m i l a r o b s e r v a t i o n s had a l s o been made f o r s k i n tumors, but not a l l types o f tumors show t h i s a s s o c i a t i o n w i t h


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d i e t a r y f a t (7). Much of t h i s work was done i n t h e 1940's and e a r l y 1950's, and t h e r e were few p u b l i c a t i o n s on the s u b j e c t d u r i n g the decade p r i o r t o our f i r s t experiment.


E p i d e m i o l o g i c a l Data

on D i e t and C a r c i n o g e n e s i s

The r e s u l t s of t h a t experiment s t i m u l a t e d us t o look f o r d a t a on d i e t a r y f a t i n r e l a t i o n t o b r e a s t c a n c e r i n human p o p u l a t i o n s , and we found t h a t m o r t a l i t y from b r e a s t c a n c e r i n d i f f e r e n t c o u n t r i e s showed a s t r o n g p o s i t i v e c o r r e l a t i o n w i t h the l e v e l o f f a t i n the d i e t ( 8 ) . T h i s c o r r e l a t i o n was noted a t about the same time by Lea (90 and Wynder (jLO). M o r t a l i t y from c a n c e r a t o t h e r s i t e s , such as the p r o s t a t e , c o l o n , rectum, ovary and pancreas i s a l s o p o s i t i v e l y c o r r e l a t e d w i t h d i e t a r y f a t , but t h e r e i s l i t t l e c o r r e l a t i o n w i t h c a n c e r a t o t h e r s i t e s , such as esophagus and stomach, and a n e g a t i v e c o r r e l a t i o n w i t h l i v e r c a n c e r (J)* More r e c e n t experiments w i t h a n i m a l s have shown t h a t h i g h - f a t d i e t s can a l s o enhance t u m o r i g e n e s i s a t s i t e s such as the c o l o n (11) and pancreas (1^2). As i n the case o f mammary c a n c e r , the e x p e r i m e n t a l r e s u l t s a r e s u p p o r t e d by e p i d e m i o l o g i c a l d a t a and t h i s has s t i m u l a t e d much i n t e r e s t i n the r o l e o f d i e t a r y f a t i n c a r c i n o g e n e s i s . In human d i e t s , o t h e r v a r i a b l e s such as t o t a l c a l o r i e s and d i e t a r y p r o t e i n , p a r t i c u l a r l y animal p r o t e i n , a r e p o s i t i v e l y c o r r e l a t e d with d i e t a r y f a t (Table I ) . I t i s t h e r e f o r e not s u r p r i s i n g t h a t these d i e t a r y v a r i a b l e s have a l s o shown a s t r o n g p o s i t i v e c o r r e l a t i o n w i t h m o r t a l i t y from cancer a t s i t e s such as the b r e a s t (]_) > A l t h o u g h experiments w i t h animals have shown t h a t t u m o r i g e n e s i s can be i n h i b i t e d by r e s t r i c t i n g c a l o r i c i n t a k e , i n most cases the r e s t r i c t i o n has been r a t h e r severe and p a i r e d - f e e d i n g experiments have i n d i c a t e d t h a t d i e t a r y f a t can a f f e c t t u m o r i g e n e s i s i n d e p e n d e n t l y o f c a l o r i c i n t a k e ( 7 ) . I n c r e a s i n g the l e v e l o f p r o t e i n i n the d i e t can enhance t u m o r i g e n e s i s i n a n i m a l s , b u t v e r y h i g h l e v e l s tend t o be i n h i b i t o r y , and t h e r e i s l i t t l e e v i d e n c e t h a t the type o f p r o t e i n i n the d i e t s i g n i f i c a n t l y a f f e c t s tumor development (13,14). In g e n e r a l , the s t u d i e s on e x p e r i m e n t a l animals support the c o n c l u s i o n t h a t d i e t a r y f a t has a g r e a t e r e f f e c t on t u m o r i g e n e s i s than e i t h e r c a l o r i c i n t a k e o r d i e t a r y p r o t e i n . Mechanism o f A c t i o n o f D i e t a r y F a t S t u d i e s on mammary tumors have shown t h a t the e f f e c t o f d i e t a r y f a t can be demonstrated w i t h spontaneous tumors and w i t h tumors induced by a v a r i e t y o f c h e m i c a l o r p h y s i c a l agents (15). Furthermore, experiments i n our l a b o r a t o r y have shown t h a t d i e t a r y f a t e f f e c t i v e l y i n c r e a s e s the y i e l d of mammary tumors induced i n r a t s by DMBA, even when t h e h i g h - f a t d i e t i s f i r s t i n s t i t u t e d one t o two weeks a f t e r treatment w i t h a c a r c i n o g e n (_7). These o b s e r v a t i o n s suggest t h a t d i e t a r y f a t i s n o t i n v o l v e d i n tumor i n i t i a t i o n b u t a c t s by p r o v i d i n g a more f a v o r a b l e environment f o r p r o l i f e r a t i o n o f tumor c e l l s . The exact mechanism o f a c t i o n i s not known, but v a r i o u s p o s s i b i l i t i e s have been suggested. Mammary t u m o r i g e n e s i s i s c l e a r l y i n f l u e n c e d by hormones, and h i g h - f a t d i e t s may a l t e r the hormonal p a t t e r n i n ways t h a t f a v o r tumor growth (16,17). I t seems l e s s l i k e l y t h a t a hormonal mechanism would be i n v o l v e d i n e f f e c t s o f d i e t a r y f a t



XENOBIOTIC METABOLISM: NUTRITIONAL EFFECTS

Figure

1.

NO. OF RATS

21

DIETARY FAT

0.5% CORN OIL

Influence

from Gammal e t a l .

Table

I.

of d i e t

21

22

20% COCONUT OIL

20% CORN OIL

on hormone-dependent c a n c e r s .

Data

(4).

Correlation

C o e f f i c i e n t s Between

Dietary

Variables Total

Animal

Animal

Total

Fat

Fat

Protein

Calories Protein

Total

Vegetal

Carbo-

Fat

hydrate

Animal Fat

+0.951

Animal Protein

+0.931

+0.931

Total Calories

+0.878

+0.841

Total Protein

+0.801

+0.777

+0.784

Vegetal Fat

+0.402

-0.099

+0.224_ +0.335

+0.286

Carbohydrate

-0.078

-0.070

-0.075

+0.071

+0.182

-0.044

Vegetal Protein

-a 268

-0.300

-0.360

+0.018

+0.264

+0.069

+0.827 +0.867

+0.413

P < 0.01 p < o.05 Note:

Based

on f o o d

balance

sheets

f o r 132 c o u n t r i e s ( s e e

Reference 13).


14.

CARROLL


181


on tumors o f non-endocrine t i s s u e s . I n the case o f c o l o n tumors, f o r example, d i e t a r y f a t may a c t by i n c r e a s i n g the f l o w o f b i l e a c i d s which can serve as promoters o f t u m o r i g e n e s i s (18). E f f e c t s o f D i f f e r e n t Types o f D i e t a r y F a t . As i n d i c a t e d above, our f i r s t d i e t a r y experiment on mammary c a r c i n o g e n e s i s showed t h a t a h i g h - p o l y u n s a t u r a t e d f a t d i e t g r e a t l y i n c r e a s e d the tumor y i e l d , w h i l e a h i g h - s a t u r a t e d f a t d i e t had no s i g n i f i c a n t e f f e c t . Subsequent experiments p r o v i d e d f u r t h e r evidence t h a t p o l y u n s a t u r a t e d f a t s a r e more e f f e c t i v e than s a t u r a t e d f a t s i n promoting mammary t u m o r i g e n e s i s ( 1 9 ) . T h i s d i f f e r e n c e appears t o be r e l a t e d t o a requirement f o r p o l y u n s a t u r a t e d f a t t y a c i d s which i s not met by the s m a l l amounts p r e s e n t i n n a t u r a l l y - o c c u r r i n g s a t u r a t e d f a t s , such as beef t a l l o w and coconut o i l . I n f u r t h e r e x p e r i m e n t s , d i e t s c o n t a i n i n g 3% p o l y u n s a t u r a t e d f a t and 17% s a t u r a t e d f a t were found t o promote mammary t u m o r i g e n e s i s as e f f e c t i v e l y as d i e t s c o n t a i n i n g 20°L p o l y u n s a t u r a t e d f a t ( 2 0 ) . L i n o l e i c a c i d appeared t o be c a p a b l e o f s a t i s f y i n g the requirement f o r p o l u n s a t u r a t e d f a t t y a c i d s , but a f i s h o i l c o n t a i n i n g p o l y u n s a t u r a t e d f a t t y a c i d s d e r i v e d m a i n l y from l i n o l e n i c a c i d was a l s o e f f e c t i v e , so t h e requirement may not be s p e c i f i c f o r n-6 f a t t y a c i d s ( 2 1 ) . P o l y u n s a t u r a t e d f a t has a l s o been found t o be more e f f e c t i v e than s a t u r a t e d f a t i n promoting the development o f p a n c r e a t i c tumors i n r a t s (1_2 ) . S i m i l a r r e s u l t s have been r e p o r t e d r e c e n t l y f o r c o l o n c a n c e r (22^), a l t h o u g h e a r l i e r experiments had i n d i c a t e d t h a t s a t u r a t e d and p o l y u n s a t u r a t e d f a t s were about e q u a l l y e f f e c t i v e a t h i g h l e v e l s o f i n t a k e (11). I t thus appears t h a t t h e r e may be a g e n e r a l requirement f o r p o l y u n s a t u r a t e d f a t t y a c i d s i n promotion o f c a r c i n o g e n e s i s by d i e t a r y f a t . S i n c e p o l y u n s a t u r a t e d f a t s a r e p r e s e n t i n s u b s t a n t i a l amounts i n the p h o s p h o l i p i d s o f c e l l membranes, and s i n c e c e l l u l a r p r o l i f e r a t i o n r e q u i r e s f o r m a t i o n of new membranes, t h i s might e x p l a i n t h e requirement f o r p o l y u n s a t u r a t e d f a t t y a c i d s i n tumor p r o m o t i o n , b u t t h e r e a r e a l s o o t h e r p o s s i b i l i t i e s . F o r example, t h e r e i s evidence t h a t c e l l - m e d i a t e d immune responses a r e i n h i b i t e d by l i n o l e i c a c i d , and reduced r e s p o n s i v e n e s s o f the immune system c o u l d h e l p t o promote tumorigenesis (23). Polyunsaturated f a t t y acids are r e l a t i v e l y susceptible to o x i d a t i o n and can g i v e r i s e t o many d i f f e r e n t types o f o x i d a t i o n p r o d u c t s i n the body as a r e s u l t o f b o t h enzymatic and non-enzymatic p r o c e s s e s . These i n c l u d e l i p i d p e r o x i d e s and such b i o l o g i c a l l y - a c t i v e p r o d u c t s as p r o s t a g l a n d i n s , thromboxanes and l e u k o t r i e n e s . There i s e v i d e n c e t h a t p r o s t a g l a n d i n s can a c t as promoters o f t u m o r i g e n e s i s (2A), and p r o s t a g l a n d i n s y n t h e s i s i n h i b i t o r s a r e c a p a b l e o f p r e v e n t i n g the promotion o f mammary t u m o r i g e n e s i s by h i g h - f a t d i e t s (25-27). I f l i p i d o x i d a t i o n i s a f a c t o r i n promotion o f t u m o r i g e n e s i s by d i e t a r y f a t , one might expect the p r o c e s s t o be i n h i b i t e d by d i e t a r y a n t i o x i d a n t s . T h i s t o p i c i s d i s c u s s e d i n more d e t a i l elsewhere i n t h i s symposium ( 2 8 ) , but the r e s u l t s have not p r o v i d e d c l e a r - c u t answers t o the q u e s t i o n . Some o f the s y n t h e t i c a n t i o x i d a n t s such as b u t y l a t e d h y d r o x y t o l u e n e (BHT) appear t o i n h i b i t the promotion o f t u m o r i g e n e s i s by d i e t a r y f a t , but r e s u l t s w i t h v i t a m i n E, a n a t u r a l l y - o c c u r r i n g a n t i o x i d a n t , have been l a r g e l y n e g a t i v e ( 2 9 ) .


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R e v e r s a l o f Promoting

E f f e c t of Dietary Fat

C a r c i n o g e n e s i s i s now g e n e r a l l y c o n s i d e r e d t o be a m u l t i s t a g e p r o c e s s ( 3 0 ) . The f i r s t s t a g e , i n i t i a t i o n , i s thought t o o c c u r r a p i d l y and t o i n v o l v e an a l t e r a t i o n o f the genome, which i s e s s e n t i a l l y i r r e v e r s i b l e . Subsequent p r o l i f e r a t i o n o f t r a n s f o r m e d c e l l s d u r i n g the p r o m o t i o n a l phase appears t o be q u i t e s u s c e p t i b l e t o e n v i r o n m e n t a l f a c t o r s . Promotion o c c u r s over a much l o n g e r time p e r i o d , r e q u i r e s r e p e a t e d exposure t o t h e promoting agent, and i s p o t e n t i a l l y r e v e r s i b l e , a t l e a s t d u r i n g the e a r l y s t a g e s . Experiments i n our own and o t h e r l a b o r a t o r i e s have p r o v i d e d e v i d e n c e t h a t the enhancement o f mammary t u m o r i g e n e s i s by h i g h - f a t d i e t s can be l a r g e l y p r e v e n t e d by s u b s t i t u t i n g a l o w - f a t d i e t a f t e r s e v e r a l months o f f e e d i n g a h i g h - f a t d i e t (31-33). T h i s i n d i c a t e s t h a t many o f t h e s i t e s i n i t i a t e d by exposure t o c a r c i n o g e n a r e p r e v e n t e d from d e v e l o p i n g i n t o tumors by t h i s p r o c e d u r e . R e s u l t s such as t h i s suggest the p o s s i b i l i t y t h a t p o t e n t i a l tumors may l i k e w i s e be p r e v e n t e d from d e v e l o p i n g i n human p o p u l a t i o n s by r e d u c i n g t h e f a t c o n t e n t of t h e d i e t . I t may a l s o be p o s s i b l e t o p r e v e n t o r a t l e a s t d e l a y the development o f m e t a s t a t i c l e s i o n s , which c o n s t i t u t e the major t h r e a t i n b r e a s t c a n c e r and o f t e n i n o t h e r types o f c a n c e r as well. In t h i s c o n n e c t i o n , i t i s o f i n t e r e s t t h a t c a n c e r i n c i d e n c e d e c r e a s e d i n England and Wales w i t h the i n t r o d u c t i o n o f food r a t i o n i n g i n 1940, and remained a t a lower l e v e l f o r about 25 y e a r s ( 3 4 ) . B r e a s t c a n c e r o c c u r s much l e s s f r e q u e n t l y i n Japanese women than i n American women, and t h e r e i s a l s o e v i d e n c e t h a t Japanese b r e a s t c a n c e r p a t i e n t s have l o n g e r s u r v i v a l times than those i n the United States (35). In the animal experiments r e f e r r e d t o above, i n h i b i t i o n o f t u m o r i g e n e s i s was a c h i e v e d by r e s t r i c t i o n o f d i e t a r y f a t t o a degree t h a t would n o t be a c c e p t a b l e i n human d i e t s . Another experiment was t h e r e f o r e c a r r i e d out i n our l a b o r a t o r y t o t e s t t h e e f f e c t o f a more moderate decrease i n d i e t a r y f a t ( 3 6 ) . F o r t h i s purpose, r a t s were t r e a t e d w i t h DMBA a t 50 days o f age and, b e g i n n i n g one week l a t e r , were f e d a h i g h - p o l y u n s a t u r a t e d f a t d i e t c o n t a i n i n g 20% by weight o f s u n f l o w e r s e e d o i l t o promote mammary tumor development. A f t e r seven weeks on t h i s d i e t , when about o n e - t h i r d o f the r a t s had developed tumors, they were d i v i d e d i n t o 5 groups o f 31 r a t s each, w i t h tumorb e a r i n g r a t s d i v i d e d e q u a l l y among t h e d i f f e r e n t groups. One group was c o n t i n u e d on t h e h i g h - p o l y u n s a t u r a t e d f a t d i e t , one group was g i v e n a f a t - f r e e d i e t , and the o t h e r t h r e e groups were f e d d i e t s c o n t a i n i n g 10% l a r d , 10% b u t t e r and 10% coconut o i l r e s p e c t i v e l y . F i v e months l a t e r , the group t h a t remained on t h e h i g h - p o l y u n s a t u r a t e d f a t d i e t had s i g n i f i c a n t l y more tumors than any o f the o t h e r groups, and t h e d i e t s c o n t a i n i n g 10% f a t suppressed t u m o r i g e n e s i s a t l e a s t as e f f e c t i v e l y as the f a t - f r e e d i e t ( F i g u r e 2). In t h i s experiment, t h e type o f f a t as w e l l as t h e amount was changed because e a r l i e r s t u d i e s had shown t h a t s a t u r a t e d f a t s were l e s s e f f e c t i v e promoters o f mammary c a r c i n o g e n e s i s than p o l y u n s a t u r a t e d f a t s . L a r d , however, has a h i g h e r c o n t e n t of l i n o l e i c a c i d than e i t h e r b u t t e r o r coconut o i l and i n c r e a s e d the tumor y i e l d almost as much as p o l y u n s a t u r a t e d f a t s when f e d a t the 20% l e v e l


CARROLL


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14.

F i g u r e 2. I n f l u e n c e o f d i e t on hormone-dependent from Kalamegham and C a r r o l l ( 3 6 ) .

cancers.


Data

XENOBIOTIC M E T A B O L I S M : N U T R I T I O N A L E F F E C T S


184

(19,20), but s u p p r e s s e d t u m o r i g e n e s i s to about the same extent as the more s a t u r a t e d f a t s when f e d at the 10% l e v e l i n the p r e s e n t e x p e r i m e n t . T h i s d i f f e r e n c e may be r e l a t e d to the lower i n t a k e of t o t a l f a t , of p o l y u n s a t u r a t e d f a t t y a c i d s , or b o t h . N o r t h American d i e t s t y p i c a l l y c o n t a i n about 40% of energy as f a t (3^7), c o r r e s p o n d i n g to a p p r o x i m a t e l y 20% by w e i g h t , w i t h a degree of u n s a t u r a t i o n somewhat g r e a t e r than t h a t of l a r d ( 3 8 ) . I t would t h e r e f o r e be of i n t e r e s t to c a r r y out an experiment s i m i l a r t o t h a t d e s c r i b e d above i n which t u m o r i g e n e s i s i s f i r s t promoted by a d i e t c o n t a i n i n g 20% of f a t h a v i n g t h i s degree of u n s a t u r a t i o n . The e f f e c t on t u m o r i g e n e s i s of r e d u c i n g the f a t c o n t e n t w i t h o u t changing i t s c o m p o s i t i o n c o u l d then be i n v e s t i g a t e d . The r e s u l t s would be of i n t e r e s t i n r e l a t i o n to e f f e c t s of d i e t a r y f a t on c a r c i n o g e n e s i s i n humans, s i n c e e p i d e m i o l o g i c a l d a t a i n d i c a t e t h a t m o r t a l i t y from b r e a s t c a n c e r and s e v e r a l o t h e r types of c a n c e r c o r r e l a t e s b e t t e r w i t h the amount r a t h e r than the type of d i e t a r y f a t ( 3 9 ) . In r e c e n t y e a r s b r e a s t c a n c e r m o r t a l i t y has, i f a n y t h i n g , shown a tendency to i n c r e a s e ( 4 0 ) , i n d i c a t i n g t h a t c u r r e n t methods of treatment are h a v i n g r e l a t i v e l y l i t t l e impact on t h i s d i s e a s e . The e p i d e m i o l o g i c a l data n e v e r t h e l e s s show l a r g e d i f f e r e n c e s i n the m o r t a l i t y r a t e s i n d i f f e r e n t c o u n t r i e s , which are s t r o n g l y c o r r e l a t e d w i t h d i e t a r y f a t i n the food s u p p l i e s . I t i s e v i d e n t t h a t new approaches are r e q u i r e d to reduce the death t o l l from b r e a s t c a n c e r i n the more a f f l u e n t c o u n t r i e s of the w o r l d , and one way might be to reduce d i e t a r y f a t i n t a k e as r e c e n t l y recommended by the NRC-NAS Committee on D i e t , N u t r i t i o n and Cancer ( 1 4 ) . The main source of f a t i n the N o r t h American d i e t i s the v i s i b l e f a t s and o i l s used as s p r e a d s , c o o k i n g f a t s and s a l a d o i l s . Other major s o u r c e s are meats and d a i r y p r o d u c t s ( 4 0 ) . Foods such as eggs and nuts are r e l a t i v e l y h i g h i n f a t but are not e a t e n i n s u f f i c i e n t q u a n t i t i e s to make a l a r g e c o n t r i b u t i o n t o t o t a l d i e t a r y f a t . Most o t h e r d i e t a r y components, i n c l u d i n g c e r e a l p r o d u c t s , f r u i t s and v e g e t a b l e s , are q u i t e low i n f a t . I t i s thus r e l a t i v e l y easy to i d e n t i f y h i g h - f a t foods but more d i f f i c u l t to a c h i e v e a s u b s t a n t i a l r e d u c t i o n i n d i e t a r y f a t because i t p r o v i d e s q u a l i t i e s of t a s t e and s a t i e t y t h a t add to the enjoyment of e a t i n g . A c l e a r d e m o n s t r a t i o n t h a t r e d u c i n g the l e v e l of d i e t a r y f a t can d e c r e a s e the r i s k of c a n c e r i n humans would no doubt p r o v i d e much g r e a t e r i n c e n t i v e f o r t h i s type of d i e t a r y m o d i f i c a t i o n . I t would be v e r y d i f f i c u l t to o b t a i n such e v i d e n c e i n a f r e e - l i v i n g p o p u l a t i o n , but i t might be p o s s i b l e w i t h groups of h i g h - r i s k i n d i v i d u a l s . A h i g h p r o p o r t i o n of b r e a s t c a n c e r p a t i e n t s e x p e r i e n c e r e c u r r e n c e of the d i s e a s e from m e t a s t a t i c c e l l s shed from the p r i m a r y tumor. S i n c e d i e t a r y f a t appears to a c t by s t i m u l a t i n g the p r o l i f e r a t i o n of tumor c e l l s , i t seems p o s s i b l e t h a t r e c u r r e n c e might be d e l a y e d or even p r e v e n t e d by r e d u c i n g f a t i n t a k e . With r e c u r r e n c e as an end p o i n t , i t may be p o s s i b l e to o b t a i n d e f i n i t i v e e v i d e n c e of the p o t e n t i a l b e n e f i t s of a l o w - f a t d i e t i n b r e a s t c a n c e r . C l i n i c a l t r i a l s a l o n g these l i n e s are a l r e a d y b e i n g suggested (35,41). Acknowledgment Support by the N a t i o n a l acknowledged.

Cancer I n s t i t u t e of Canada i s g r a t e f u l l y


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RECEIVED

August 17,

1984


Xenobiotic Metabolism: Nutritional Effects - ACS Publications

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