Dietary Factors Affecting Biological Responses to ... - ACS Publications

13 Dietary Factors Affecting Biological Responses to Esophageal and Colon Chemical Carcinogenesis

Downloaded by TUFTS UNIV on June 2, 2018 | https://pubs.acs.org Publication Date: May 6, 1985 | doi: 10.1021/bk-1985-0277.ch013

PAUL M. NEWBERNE Massachusetts Institute of Technology, Cambridge, MA 02139 Cancer of the esophagus and colon are frequent in populations of the western world and are associated with diet and lifestyle. There is also a high incidence of esophageal cancer in some areas of developing countries; these areas are restricted to relatively small geographic locations within countries and support the concept that the etiology is related to the environment. In the United States and in other western countries esophageal cancer is correlated with alcohol and tobacco consumption. In developing countries correlations exist between malnutrition and environmental contaminants. The incidence of colon cancer is high in western populations except for Japan and low in most developing nations. The high incidence is associated with high dietary fat. Low fiber intake has also been associated with the high colon cancer incidence in some populations. The epidemiologic data, relative to dietary fiber, has been supported by animal studies but experiments with dietary fat have been conflicting and generally do not indicate a fat effect. Other dietary factors which associate with colon cancer in animal studies are deficits of lipotropes and of vitamin A. Cancer of the esophagus is not amenable to satisfactory surgical or chemical intervention and must therefore be addressed by searching for preventative measures. This type of neoplasm provides a unique epidemiologic model for the study of cancer causation and offers a means to learn more about initiation and promotion of this unique tumor. The incidence of esophageal cancer varies widely in different areas of the world (1). There is as much as 300-fold variation from areas of low incidence to that of the highest rates in places such as the southern Caspian littoral in Iran, the Transkei in South Africa and in some parts of China. These epidemiological observations provide opportunities to identify environmental factors and to test these real or potential factors in appropriate animal models (2). 0097-6156/85/0277-0163S06.00/0 © 1985 American Chemical Society

Finley and Schwass; Xenobiotic Metabolism: Nutritional Effects ACS Symposium Series; American Chemical Society: Washington, DC, 1985.


164

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

A number o f i n v e s t i g a t o r s have found a c o n s i s t e n t r e l a t i o n s h i p between m o r t a l i t y from e s o p h a g e a l c a n c e r and e t h a n o l consumption (3-5). These o b s e r v a t i o n s have been s u p p o r t e d by c a s e - c o n t r o l s t u d i e s (6-8) which have shown s t r o n g c o r r e l a t i o n s between a l c o h o l c o n sumption and e s o p h a g e a l c a n c e r but w i t h o u t c o n s i s t e n t a s s o c i a t i o n w i t h any s p e c i f i c t y p e o f beverage (9,10) . A l c o h o l consumption cannot account f o r the p a t t e r n o f e s o p h a g e a l c a n c e r i n A s i a and A f r i c a , however (11-13). Correlation studies i n I r a n suggest t h a t t h e i n t a k e s o f p u l s e s , g r e e n v e g e t a b l e s , f r e s h f r u i t , a n i m a l p r o t e i n , v i t a m i n A, v i t a m i n C and r i b o f l a v i n a r e lower i n a r e a s o f h i g h r i s k (14,15) . S i m i l a r s t u d i e s i n C h i n a have i m p l i c a t e d low i n t a k e s o f t r a c e elements (molybdenum), a n i m 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 , f a t , c a l c i u m , and r i b o f l a v i n ( 1 3 ) . T h e r e was a l s o a r e p o r t e d c o n c o m i t a n t i n t a k e o f f o o d s contaminated w i t h Nn i t r o s o compounds and f u n g a l t o x i n s . Marasas e t a l (16) have a l s o r e p o r t e d mycotoxin c o n t a m i n a t i o n o f f o o d s i n a r e a s o f South A f r i c a where a h i g h i n c i d e n c e o f e s o p h a g e a l c a n c e r i s f o u n d . L i n e_t a l (17) o b s e r v e d low c o n c e n t r a t i o n s o f z i n c i n serum, h a i r , and e s o p h a g e a l t i s s u e i n p a t i e n t s w i t h o t h e r t y p e s o f c a n c e r o r with other diseases (Table I ) . Table I.

Z i n c L e v e l s i n Serum, H a i r and E s o p h a g e a l E s o p h a g e a l Cancer P a t i e n t s

T i s s u e s From

Zinc Concentrations ( g/100 ml o r g)

Normal S u b j e c t s P a t i e n t s With: E s o p h a g e a l Cancer Other Cancers Other D i s o r d e r s

Serum 102.7±18.5

Hair 195.0129.0

Esophageal Esophagus Tumor 110.0122.4 160.0128.7

78.0114.9 114.4±31.8 96.2115.0

162.0133.0 169.0137.0 212.0148.0

149.0118

Taken from d a t a on a c c i d e n t a l d e a t h s , u n r e l a t e d t o t h e c a n c e r s t u d y . L i n e t a l . , 1977, a b r i d g e d .

248.0117.0

esophageal

I n summary, a l c o h o l , t o b a c c o , and a number o f d i e t a r y n u t r i e n t s and c o n t a m i n a n t s have been i m p l i c a t e d i n esophageal c a n c e r by epidemi o l o g i c a l s t u d i e s i n s e v e r a l d i f f e r e n t g e o g r a p h i c a r e a s o f the w o r l d where t h i s t y p e tumor i s found i n h i g h i n c i d e n c e i n human p o p u l a t i o n s . C u r r e n t l y , t h e r e a r e no c o n v i n c i n g d a t a a v a i l a b l e f o r s p e c i f i c e t i o l o g i c f a c t o r s but some a r e s u g g e s t e d from e p i d e m i o l o g i c o b s e r v a t i o n s ; t h e s e a r e now b e i n g t e s t e d i n a n i m a l models. R e s u l t s o f some o f t h e s e s t u d i e s w i l l be b r i e f l y d e s c r i b e d below. S t u d i e s have been d e s i g n e d t o t e s t t h e s u g g e s t i o n s o f L i n est a l (17) t h a t z i n c d e f i c i e n c y , w h i c h a l o n e damages the esophagus, enhances c h e m i c a l l y - i n d u c e d e s o p h a g e a l c a n c e r . In a s e r i e s o f s t u d i e s i n r a t s , u s i n g m e t h y l b e n z y l n i t r o s a m i n e (MBN) as the c a r c i n o g e n we have c l e a r l y shown t h a t d i e t a r y z i n c d e f i c i e n c y lowers t h e c o n c e n t r a t i o n o f z i n c i n serum, h a i r and e s o p h a g e a l t i s s u e s , and markedly enhances t h e i n d u c e d e s o p h a g e a l c a n c e r (18-20). Table I I l i s t s data t y p i c a l o f r e s u l t s from our e a r l i e r s t u d i e s . Z i n c l e v e l s were s i g n i f i c a n t l y lower i n t h e serum, h a i r and esophagus o f z i n c - d e f i c i e n t r a t s , w i t h


13.

NEWBERNE

Esophageal and Colon Chemical Carcinogenesis

165

o r w i t h o u t t r e a t m e n t w i t h MBN. Z i n c d e f i c i e n c y a l o n e o r MBN alone r e s u l t e d i n lowered esophageal z i n c c o n c e n t r a t i o n . Both d i e t a r y def i c i e n c y and t r e a t m e n t w i t h MBN s e v e r e l y d e p l e t e d e s o p h a g e a l z i n c content. Table I I .

Z i n c L e v e l s i n R a t s Fed a Z i n c D e f i c i e n t D i e t and T r e a t e d W i t h M e t h y l b e n z y l n i t r o s a m i n e (MBN) Serum Hair Esophagus (yg/100 ml) (ppm) (ppm) Control 101.9 ± 12.7 223.7 ± 25.5 211.3 ± 38.8 C o n t r o l + MBN 124.4 ± 12.9 202.8 ± 11.4 156.2 ± 12.3 Zinc D e f i c i e n t 38.3 ± 11.6 165.2 ± 15.2 136.6 ± 16.8 Z i n c D e f i c i e n t + MBN 46.8 ± 15.5 160.8 ± 15.6 126.0 ± 37.2


a

d i f f e r e n c e s i n z i n c c o n c e n t r a t i o n s o f serum and h a i r o f c o n t r o l and z i n c d e f i c i e n t groups s i g n i f i c a n t p < 0.01. D a t a e x p r e s s e d as mean ± S.D. Table I I I l i s t s r e s u l t s of c a r c i n o g e n i c i t y studies associated with zinc deficiency. These r a t s were g i v e n 17 doses o f MBN, beginn i n g a t seven weeks o f age. F i f t y e i g h t days a f t e r the f i r s t dose of MBN, a l l z i n c - d e f i c i e n t r a t s had d e v e l o p e d tumors of the esophagus, 83% o f which were i n v a s i v e c a r c i n o m a s . F i v e weeks l a t e r , a l l d e f i c i e n t r a t s had tumors, 33% o f which were i n v a s i v e , c l e a r l y , a marked enhancement o f c a r c i n o g e n e s i s by z i n c d e f i c i e n c y . Table I I I .

E s o p h a g e a l Tumor I n c i d e n c e i n C o n t r o l and Z i n c D e f i c i e n t R a t s Exposed to M e t h y l b e n z y l n i t r o s a m i n e MBN, mg/kg Time, 1 s t Dose Tumor I n c i d e n c e Body Wt. MBN to S a c r i f i c e No./% Diet Carcinoma Papilloma 6/6(100) Zinc D e f i c i e n t 58 5/6(83) 34 ad l i b i t u m Control, Pair-fed 2/6(33) 58 34 0/6(0) Zinc D e f i c i e n t 4/12(33) 12/12(100) 34 93 ad l i b i t u m 0/12 8/12(66) Control, Pair-fed 93 34 From Fong e t a l . , 1978, by p e r m i s s i o n . C o n s u l t r e f e r e n c e f o r d e t a i l s . I n f o l l o w - u p s t u d i e s (19) w i t h an a d d i t i o n a l r i s k f a c t o r ( a l c o h o l ) the r e s u l t s c o n f i r m e d e a r l i e r o b s e r v a t i o n s and a d d i t i o n a l s i g n i ficant findings. T a b l e IV l i s t s the s a l i e n t f e a t u r e s o f the s t u d y . Z i n c d e f i c i e n c y s i g n i f i c a n t l y enhanced c a r c i n o g e n e s i s . Alcohol tended t o f u r t h e r enhance c a n c e r i n c i d e n c e and 1 3 - c i s r e t i n o i c a c i d o f f e r e d no p r o t e c t i o n . S w i t c h i n g the z i n c d e f i c i e n t group from d e f i c i e n t (7 ppm Zn) t o the c o n t r o l d i e t (60 ppm) a f t e r exposure to the carcinogen afforded s i g n i f i c a n t protection, i n d i c a t i n g protective e f f e c t s d u r i n g b o t h the i n i t i a t i o n and the p r o m o t i o n s t a g e s o f c a r cinogenesis . A p a r t i a l e x p l a n a t i o n f o r the e f f e c t s o f a l c o h o l on z i n c s t a t u s may r e s i d e i n the o b s e r v a t i o n s t h a t : 1) a l c o h o l i n c r e a s e s z i n c exc r e t i o n (21) , and 2) the i n c r e a s e d z i n c e x c r e t i o n p r e c i p i t a t e s a c r i s i s r e s u l t i n g i n a c o n d i t i o n e d d e f i c i e n c y i n the esophagus and g r e a t er s u s c e p t i b i l i t y to carcinogenesis.


166

XENOBIOTIC METABOLISM: NUTRITIONAL E F F E C T S

T a b l e IV.

Tumor I n c i d e n c e Induced by MBN i n R a t s D e f i c i e n t i n Z i n c and G i v e n E t h y l A l c o h o l and 1 3 - c i s R e t i n o i c A c i d Treatment, 4% A l c o h o l i n 13-cis No. R a t s W i t h Z i n c Content MBN D r i n k i n g Water Retinoic Acid Tumors, % C o n t r o l , 60 ppm 0/12 0 C o n t r o l , 60 ppm + 40.0 14/35 D e f i c i e n t , 7 ppm + 25/33 75.7 60 ppm C o n t r o l , 51.4 18/35 D e f i c i e n t 7 ppm to Post Dosing Deficient + + 29/34 85.3 Deficient + + + 94.3 33/35 From G a b r i a l e t a l . , 1982, abridged.

-

-

-


-

I n comparing the t i s s u e z i n c c o n c e n t r a t i o n i n r a t s f e d e i t h e r a m a r g i n a l l y z i n c - d e f i c i e n t d i e t or a z i n c - d e f i c i e n t d i e t plus a l c o h o l we have o b s e r v e d t h a t the s i m p l e a d d i t i o n o f a l c o h o l p r e c i p i t a t e d an a c u t e d e f i c i e n c y w i t h accompanying e s o p h a g e a l l e s i o n s ( T a b l e V) ( 2 2 ) . T h e r e i s a l s o c l i n i c a l e v i d e n c e i n human p a t i e n t s (21) f o r an enhanced e x c r e t i o n o f z i n c f o l l o w i n g consumption o f a l c o h o l , w h i c h has been s u p p o r t e d by s t u d i e s i n r a t s ( 2 3 ) ( T a b l e V I ) . A marginal d e f i c i e n c y o f z i n c , when i n t e r a c t i n g w i t h a l c o h o l consumption q u i c k l y p r o g r e s s e d t o an a c u t e d e f i c i e n c y w i t h the t y p i c a l h i s t o l o g i c l e s i o n o f p a r a k e r a t o s i s o c c u r r i n g ; t h i s d i d not appear w i t h the m a r g i n a l d e f i c i e n c y alone. T a b l e V.

Comparison o f T i s s u e Z i n c C o n c e n t r a t i o n and E s o p h a g e a l E p i t h e l i u m Changes i n Z i n c D e f i c i e n t A l c o h o l (ZDA) D i e t Fed R a t s and T h e i r C o r r e s p o n d i n g Z i n c D e f i c i e n t (ZD) Fed C o n t r o l s Tissue Zinc Concentration Esophageal (ug/gm Wet Wt.) H i s t o l o g i c Findings Liver Hair Parakeratosis B a s e l i n e Animals 25.5±2.9 212.4±23.8 ZD D i e t Fed A n i m a l s 11.6±0.5 146.4±09.0 1 (11%) ZDA D i e t Fed A n i m a l s 9.0±0.5 110.0+18.3 7 (78%) From Mobarhan e t a l . , 1984

.

T a b l e V I . F e c a l Z i n c E x c r e t i o n (yg/day) i n Z i n c D e f i c i e n t E t h a n o l (ZDE) Fed A n i m a l s and T h e i r C o r r e s p o n d i n g P a i r - F e d Z i n c D e f i c i e n t (ZD) C o n t r o l s * ZDE ZD P Value (yg/day) (yg/day) NS 5.6 Day 0 5.6 51.3 + 51.3 + < .001 9.5 Day 7 31.7 + 11.9 17.9 + < .003 7.2 Day 14 12.3 + 29.1 + 17.6 < .002 3.8 Day 21 24.4 + 9.6 12.9 + < .007 Day 28 15.7 + 10.7 36.9 + 18.3 *Seven p a i r s o f a n i m a l s were s t u d i e d . Numbers a r e e x p r e s s e d as mean ± S.D. and P v a l u e s a r e d e r i v e d from a p a i r e d T - t e s t c o m p a r i s o n . Each d a t a p o i n t c o n s i s t s o f an average o f 3 d a y s ; e.g. day 7 r e p r e s e n t s an average e x c r e t i o n from days 6, 7, and 8. (23).


13.

NEWBERNE

167


A d d i t i o n a l s t u d i e s have f u r t h e r s u p p o r t e d a r o l e f o r z i n c i n the e t i o l o g y o f c a n c e r o f the esophagus (24,25) . I n the p r e s e n c e o f a z i n c d e f i c i t , the p r e c u r s o r s o f m e t h y l b e n z y l n i t r o s a m i n e (MBN) more r e a d i l y i n d u c e d b o t h e s o p h a g e a l and f o r e s t o m a c h tumors i n r a t s , compared to zinc-supplemented c o n t r o l r a t s . Table VII i l l u s t r a t e s these effects. Table V I I .

Group Ha 0.05%

MBA

I n c i d e n c e o f Tumors i n t h e Esophagus and Forestomach i n Z i n c - D e f i c i e n t and Z i n c - S u f f i c i e n t Rats Fed C o n c u r r e n t l y MBA and NaNO^ i n D r i n k i n g Water f o r 37 Weeks Weight Tumor I n c i d e n c e Diet (g) Carcinoma Papilloma Zn-Deficient ad l i b i t u m

209

± 62

4/18

12/18

Zn-Sufficient ad l i b i t u m

290

± 73

2/6

5/6


_i_

0.5%

NaN0

2

From Fong et_ a l . ,

1984,

abridged.

F u r t h e r s t u d i e s w i t h z i n c d e f i c i e n c y have demonstrated t h a t t h e d e f i c i e n c y s t a t e n o t o n l y enhances e s o p h a g e a l c a r c i n o g e n i c i t y o f MBN but can a l s o change t h e t a r g e t s i t e f o r c a r c i n o g e n e s i s by a n o t h e r c a r c i n o g e n . N - n i t r o s o d i m e t h y l a m i n e (DMN), an a c c e p t e d c a r c i n o g e n f o r the l i v e r and the k i d n e y , depending on the dose s c h e d u l e (26) w i l l i n d u c e tumors o f t h e esophagus and t h e f o r e s t o m a c h i n z i n c d e f i c i e n t r a t s (27,28). We have f e d c o n t r o l and z i n c - d e f i c i e n t r a t s t h e i r r e s p e c t i v e d i e t s and a d m i n i s t e r e d N - n i t r o s o d i m e t h y l a m i n e (DMN) a t a dose l e v e l o f 2 mg/kg t w i c e weekly f o r 3 weeks f o l l o w e d by 4 mg/kg o f t h e same c a r c i n o g e n f o r a n o t h e r 5 weeks, a t o t a l o f 52 mg/kg. A f t e r 45 weeks none o f t h e c o n t r o l r a t s had d e v e l o p e d e s o p h a g e a l o r forestomach l e s i o n s b u t , as shown i n T a b l e V I I I , most o f t h e z i n c - d e f i c i e n t r a t s d e v e l o p e d f o r e s t o m a c h l e s i o n s o r tumors (28) . Mechanisms f o r t h i s i n t e r e s t i n g o b s e r v a t i o n a r e u n c l e a r but t h e u n d e r l y i n g t o x i c o l o g y p r o b a b l y r e s i d e s i n m e t a b o l i s m a f f e c t i n g t h e s i t e o f tumor o c c u r r e n c e and t y p e o f a c t i v a t i o n o f DMN. Table V I I I .

H i s t o p a t h o l o g y o f Forestomach o f Z n - D e f i c i e n t Rats Fed DMN Number o f Rats (%) Lesion 1. E p i t h e l i a l Changes 51(100) Hyperkeratosis 45 (88) Acanthosis Focal Parakeratosis, D y s k e r a t o s i s , and/or 23 (45) Erosion/Ulceration 2. Tumors Junctional 19 (37) J u n c t i o n a l and Other A r e a s 13 (25) From Fojhg e t a l . , 1984, a b r i d g e d .



168

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

E s o p h a g e a l c a n c e r can a l s o be i n f l u e n c e d by o t h e r n u t r i e n t s . R i b o f l a v i n (B^) d e f i c i e n c y r e s u l t s i n s e v e r e changes i n t h e e p i t h e l ium o f t h e o r a l t i s s u e s and esophagus i n r a t s and p r i m a t e s . The e f f e c t s o f r i b o f l a v i n d e f i c i e n c y i n human p o p u l a t i o n s a r e w e l l known (29,30) but a n i m a l models f o r i n v e s t i g a t i o n o f consequences o f t h e d e f i c i e n c y have been used v e r y l i t t l e . Dr. Henry Foy ( p e r s o n a l communication) has drawn a t t e n t i o n t o the s e v e r e e f f e c t s o f r i b o f l a v i n d e f i c i e n c y i n t h e baboon, w i t h p a r t i c u l a r a t t e n t i o n t o the d y s p l a s i a o f t h e e p i t h e l i u m o f t h e o r a l c a v i t y and esophagus. Dr. Foy has pursued t h e s e s t u d i e s f o r many y e a r s a t t h e Wellcome R e s e a r c h L a b o r a t o r i e s i n N a i r o b i . We have o b s e r v e d s i m i l a r l e s i o n s i n t h e Rhesus monkey, and have f u r t h e r pursued t h e e f f e c t s o f r i b o f l a v i n d e f i c i e n c y i n t h e r a t . We have superimposed an e s o p h a g e a l c a r c i n o g e n (MBN) on the d e p r i v e d , damaged o r a l c a v i t y and e s o p h a g e a l e p i t h e l i u m . T a b l e IX l i s t s r e s u l t s o f a f i v e month s t u d y , emphasizing t h e p r o f o u n d enhancement the d e f i c i e n c y can have on t h e esophagus ( 3 1 ) . T a b l e IX.

R i b o f l a v i n (B ) D e f i c i e n c y i n t h e R a t : Enhanced Esophageal C a r c i n o g e n e s i s Treatment I n c i d e n c e o f Neoplasms No. % Control Diet 0.0 0/10 C o n t r o l D i e t + MBN* 8/20 40.0 B~ D e f i c i e n c y 0/20 0.0 88.0 B D e f i c i e n c y + MBN 23/26 2

*Methylbenzylnitrosamine.

Newberne,

1984.

We have not pursued mechanisms but suggest t h a t the enhancement o f c a r c i n o g e n e s i s may be r e l a t e d t o a r o l e f o r r i b o f l a v i n i n the a c t i v a t i o n o f enzymatic p r o c e s s e s i n v o l v e d w i t h m e t a b o l i c d e t o x i f i c a t i o n o f MBN, s i m i l a r t o azo r e d u c t a s e and i t s r o l e i n t h e d e t o x i f i c a t i o n o f 4-dimethylaminoazobenzene (32) . I n t h i s c a s e r i b o f l a v i n a c t i v a t e s azo r e d u c t a s e i n the l i v e r and t h i s , i n t u r n , i s a s s o c i a t e d with decreased c a r c i n o g e n i c i t y . C o n v e r s e l y , when a n i m a l s a r e dep r i v e d o f r i b o f l a v i n , t h e r e i s l e s s a c t i v e enzyme p r e s e n t t o d e t o x i f y the c h e m i c a l and t h e i n d u c t i o n o f l i v e r c a n c e r i s enhanced. A s i m i l a r p r o c e s s may be f u n c t i o n i n g i n our MBN, r i b o f l a v i n d e p r i v e d model but t h e e x a c t n a t u r e o f the mechanism r e q u i r e s a d d i t i o n a l r e s e a r c h . Colon

Cancer

S t u d i e s o f the i n c i d e n c e o f and m o r t a l i t y from c o l o n c a n c e r a t t h e i n t e r n a t i o n a l l e v e l suggest an a s s o c i a t i o n o f t h i s neoplasm w i t h t o t a l d i e t a r y f a t (33,34) . L u i e t a l (35) , s t u d y i n g t h e d i s a p p e a r a n c e r a t e o f f o o d and m o r t a l i t y from c o l o n c a n c e r between the y e a r s 1967-1973 i n 20 i n d u s t r i a l i z e d c o u n t r i e s , c o n c l u d e d t h a t t h e r e was a d i r e c t c o r r e l a t i o n o f t h i s tumor t y p e and the p e r c a p i t a i n t a k e o f t o t a l f a t , s a t u r a t e d and monounsaturated f a t and c h o l e s t e r o l . Furthermore, f i b e r i n t a k e was i n v e r s e l y c o r r e l a t e d w i t h c o l o n c a n c e r i n t h e s e s t u d i e s . Berg and Howell (36) and Howell (37) r e p o r t e d a h i g h c o r r e l a t i o n f o r meat i n t a k e and c o l o n c a n c e r , p a r t i c u l a r l y b e e f . Enstrom, on t h e o t h e r hand (38) s u g g e s t e d t h a t t r e n d s i n p e r c a p i t a i n t a k e o f b e e f



13.

NEWBERNE


169

and f a t i n t h e U n i t e d S t a t e s do n o t c o r r e l a t e w i t h t r e n d s i n i n c i dence o f and m o r t a l i t y from c o l o n c a n c e r . An e x a m i n a t i o n o f t h e crude d a t a s u p p o r t t h i s s u g g e s t i o n s i n c e b e e f consumption (and accomp a n y i n g f a t ) have i n c r e a s e d about 2 - f o l d d u r i n g t h e l a s t 20-30 y e a r s but a g e - a d j u s t e d d e a t h r a t e s from c o l o n c a n c e r have remained about the same. Bingham e t a l (39) r e l a t e d f o o d s , n u t r i e n t s and d i e t a r y f i b e r to the r e g i o n a l p a t t e r n o f d e a t h from c o l o n c a n c e r and s u g g e s t e d t h a t the p e n t o s a n f r a c t i o n o f d i e t a r y f i b e r was most s i g n i f i c a n t as a p r o t e c t i v e f i b e r component. F u r t h e r t o the p o i n t o f f i b e r r e l a t i o n s h i p s t o c o l o n c a n c e r , M a l h o t r a (40) has s u g g e s t e d t h a t t h e absence o f c o l o n c a n c e r among t h e P u n j a b i s o f N o r t h e r n I n d i a i s a r e s u l t o f a d i e t r i c h i n roughage i n c l u d i n g c e l l u l o s e and v e g e t a b l e f i b e r . There was a l s o a s u g g e s t i o n t h a t s h o r t - c h a i n f a t t y a c i d s i n fermented m i l k p r o d u c t s o f f e r e d some p r o t e c t i o n . MacLennan e t a l (41) reviewed t h e d i e t s o f a d u l t males from Kuop i o , F i n l a n d and from Copenhagan, Denmark, t h e l a t t e r where t h e i n c i dence o f c o l o n c a n c e r i s f o u r times h i g h e r than K u o p i o . Among o t h e r f i n d i n g s they n o t e d t h a t t h e e s t i m a t e d f a t consumption was s i m i l a r but f i b e r i n t a k e was h i g h e r i n Kuopio men, a s s o c i a t e d w i t h lower c o l on c a n c e r r a t e s . Selenium has been r e p o r t e d t o have a p o s i t i v e , enhancing e f f e c t (42) o r an i n v e r s e c o r r e l a t i o n between t h e i n t a k e o f s e l e n i u m and c o l o n c a n c e r (43,44) . B i r t e t a l (45) have r e p o r t e d i n h i b i t i o n o f c o l o n c a n c e r i n r a t s by d i e t a r y s e l e n i u m . The work o f P h i l l i p s e t a l (46-48) , Lyon and Sorenson (49) , Lyon e t a l (50) and K o l o n e l e t a]L (51) have p r o v i d e d c o n v i n c i n g arguments f o r a r o l e o f a number o f d i e t a r y f a c t o r s i n c o l o n c a n c e r i n man. The d a t a o f P h i l l i p s and Snowdon (48) i l l u s t r a t e as w e l l as any the r e l a t i o n o f d i e t t o c o l o n c a n c e r i n s u b s e t s o f an American p o p u l a t i o n ; t h e C a l i f o r n i a A d v e n t i s t s . T a b l e X shows t h e comparable m o r t a l i t y from l a r g e bowel c a n c e r i n C a l i f o r n i a A d v e n t i s t s comparable t o nonA d v e n t i s t s , and a l l USA w h i t e s . D e s p i t e a v e r y wide v a r i a t i o n i n meat u s e , t h e r e i s no apparent r e l a t i o n s h i p between meat use and f a t a l colon cancer. The d e f i n i t i v e s t u d i e s a r e y e t t o be done howe v e r , and, as n o t e d below, a n i m a l s t u d i e s a r e a l s o i n s e r t i n g c o n f l i c t i n g d a t a i n t o t h e a l r e a d y c o n f u s e d l i t e r a t u r e o f d i e t a r y e f f e c t s on colon cancer. I n terms o f e p i d e m i o l o g i c d a t a perhaps t h e NAS d o c u ment (1) has made t h e a p p r o p r i a t e s u g g e s t i o n s t o which t h i s i n v e s t i g a t o r would add a d i s c l a i m e r . The p o i n t s made by t h e NAS document are: 1) t h e r e may be a c a u s a l a s s o c i a t i o n o f human c o l o n c a n c e r w i t h t o t a l , perhaps s a t u r a t e d f a t ; 2) t h e r e may be a p r o t e c t i v e e f f e c t o f d i e t a r y f i b e r ; and 3) c r u c i f e r o u s v e g e t a b l e s may a f f o r d some p r o t e c t i o n a g a i n s t human c o l o n c a n c e r . A l l o f t h e s e p r e s u p p o s i t i o n s r e quire confirmation. In the c a s e o f a n i m a l s t u d i e s w i t h c o l o n c a r c i n o g e n e s i s , t h e r e a r e e q u a l l y d i s q u i e t i n g h y p o t h e s e s , none o f which have been adequately tested. F o r example, t h e r e a r e t h o s e (52,53) who suggest t h a t d i e t a r y f a t and f i b e r , and t h e consequences o f t h e s e on such p a r a meters as b i l e a c i d s and o t h e r c o n t r i b u t o r y f a c t o r s a r e the key t o c o l o n c a r c i n o g e n e s i s . These hypotheses a r e s t i l l b e i n g t e s t e d and p r e l i m i n a r y r e s u l t s s h o u l d be r e g a r d e d w i t h c a u t i o n . The a n i m a l data, d e t a i l e d below, w i l l p o i n t out b o t h e n c o u r a g i n g and d i s c o u r a g i n g a s p e c t s o f s t a t e o f the a r t e x p e r i m e n t a t i o n .


170

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

EFFECTS

T a b l e X.

L a r g e Bowel A g e - A d j u s t e d Cancer M o r t a l i t y / 1 0 0 , 0 0 0 f o r C a l i f o r n i a A d v e n t i s t s , N o n - A d v e n t i s t s and A l l USA W h i t e s , Compared t o T h e i r Meat Consumption Meat and P o u l t r y Use L a r g e Bowel Days/Week Mortality Group P e r 100,000 and Mortality/100,000 C a l i f o r n i a Adventists 32.6 None 22.7 Comparable N o n - A d v e n t i s t s 1-3 Times 27.2 50.6 P e r Week A l l Use Whites 4 o r More 19.1 57.5 Compiled from P h i l l i p s and Snowdon, 1983, a b r i d g e d , see r e f e r e n c e f o r details.


L i p i d s and

Fiber

Some o f the e a r l i e r , s i g n i f i c a n t p u b l i c a t i o n s on the r o l e o f d i e t a r y f a t i n e x p e r i m e n t a l c o l o n c a n c e r a r e t h o s e o f Reddy j i t a l (53-57). These i n v e s t i g a t o r s have r e p o r t e d t h a t r a t s f e d 5% c o r n o i l d i e t s had a h i g h e r tumor i n c i d e n c e and a l a r g e r number o f tumors per a n i m a l than t h o s e f e d a 5% l a r d d i e t . Tumor i n c i d e n c e and m u l t i p l i c i t y i n c r e a s e d w i t h h i g h e r (20%) f a t l e v e l s but the i n c i d e n c e and m u l t i p l i c i t y o f tumors were comparable w i t h c o r n o i l o r l a r d . T a b l e XI i l l u s t r a t e s some o f t h e i r o b s e r v a t i o n s . Table XI.

C o l o n Tumor I n c i d e n c e W i t h Two L e v e l s and Types o f D i e t a r y Fat Diet T o t a l Tumors Per C o l o n Tumors(%) Corn o i l , 5% 0.77 36 L a r d , 5% 0.22 17 Corn o i l , 20% 1.55 64 L a r d , 20% 1.50 67 Purina Chow 0.25 25 From Reddy e t a l . , 1976, m o d i f i e d .

Rat

One h y p o t h e s i s l i n k i n g d i e t a r y f a t t o c o l o n c a n c e r i s t h a t c h o l e s t e r o l i s c o n v e r t e d t o b i l e a c i d s w h i c h a c t as promoters o f c a r c i n o g e n e s i s ( 5 8 ) . E p i d e m i o l o g i c a l s t u d i e s have shown however, (38) t h a t when beef consumption i n the U n i t e d S t a t e s doubled (between 19401970) the i n c i d e n c e o f c o l o n c a n c e r m o r t a l i t y was v i r t u a l l y unchanged. I n a d d i t i o n , t h e i n c i d e n c e o f c o l o n c a n c e r i s the same i n Seventh Day A d v e n t i s t s , who e a t meat s p a r i n g l y (59) and Mormons, who consume a conventional d i e t (60). These e p i d e m i o l o g i c a l o b s e r v a t i o n s have suggested a m e t a b o l i c c l u e t o the e f f e c t o f f a t s which may be t h r o u g h f e c a l s t e r o i d metab o l i s m and e x c r e t i o n . These have been measured i n p o p u l a t i o n s a t h i g h and a t low r i s k f o r c o l o n c a n c e r . Table XII l i s t s r e s u l t s of one such i n v e s t i g a t i o n . The a b s o l u t e amount o f s t e r o i d s e x c r e t e d i s much lower i n c o n t r o l s u b j e c t s but t h i s c o u l d r e f l e c t the h e a l t h s t a t u s o f the i n d i v i d u a l s . I n the n e u t r a l s t e r o l f r a c t i o n the r a t i o of c h o l e s t e r o l to i t s m e t a b o l i t e s i s h i g h e r i n c o l o n cancer p a t i e n t s , perhaps i n d i c a t i n g i n a b i l i t y t o m e t a b o l i z e c h o l e s t e r o l . Comparisons of f e c a l s t e r i o d s i n populations of varying s u s c e p t i b i l i t y to colon c a n c e r have a l s o g i v e n v a r i a b l e r e s u l t s .


13.

NEWBERNE

Table XII.


F e c a l S t e r o i d s i n Three Groups o f S u b j e c t s mg/g Dry Feces Adenomatous Control (40)* Polyps (15)*


Steroid Neutral Cholesterol Coprostanol Coprostanone lidic Cholic Chenodeoxycholic Deoxycholic Lithocholic From Reddy, 1979, a b r i d g e d .

171

Colon Cancer ( 3 5 ) *

6.4 19.6 4.0

12.6 18.7 3.9

0.4 0.4 0.2 0.3 0.3 3.7 3.1 5.4 *Number s u b j e c t s .

0.5 0.5 7.0 6.5

3.2 12.9 1.9

I f b i l e a c i d s are indeed a r i s k f a c t o r i n c o l o n c a r c i n o g e n e s i s , s u b s t a n c e s which enhance e x c r e t i o n o f b i l e a c i d s s h o u l d i n h i b i t t h e development o f c o l o n tumors. T h i s has been t e s t e d i n e x p e r i m e n t a l animals. Bran and c e l l u l o s e i n h i b i t DMH-induced c o l o n tumors i n r a t s (61,62) . D e s p i t e tumor i n h i b i t i o n , n e i t h e r o f t h e s e f i b e r s b i n d b i l e a c i d s t o any a p p r e c i a b l e e x t e n t ( 6 3 ) . Moreover, N i g r o e t a l (64) have shown t h a t c h o l e s t y r a m i n e , a b i l e a c i d - b i n d i n g r e s i n , when added to the d i e t o f r a t s g i v e n one o f t h r e e c a r c i n o g e n s s i g n i f i c a n t l y i n c r e a s e d tumor i n c i d e n c e ( T a b l e X I I I ) . These d a t a argue a g a i n s t any d i r e c t e f f e c t o f b i l e a c i d s on c o l o n t u m o r i g e n e s i s . Table X I I I .

Cholestyramine

Carcinogen 1,2-Dimethylhydrazine

Azoxymethane Methylazoxymethanol From N i g r o e t a l . ,

1973,

and

C o l o n Cancer

Number o f C o l o n Tumors Distal Proximal Diet 1 Normal D i e t (ND) 15 Normal D i e t + 31 29 Cholestyramine (NDC) 8 ND 19 36 33 NDC 2 ND 4 18 15 NDC abridged

The i n f l u e n c e o f d i e t a r y f i b e r on c o l o n c a n c e r has been t h e subj e c t o f e x t e n s i v e i n v e s t i g a t i o n s by e p i d e m i o l o g i s t s and e x p e r i m e n t a l o n c o l o g i s t s ( 6 5 ) . The r e s u l t s from human p o p u l a t i o n s have been v a r i a b l e ; a n i m a l i n v e s t i g a t i o n s have been v a r i a b l e as w e l l b u t , i n gene r a l , p o i n t t o an e f f e c t o f f i b e r on i n d u c e d c o l o n tumors. T a b l e XIV taken from the work o f Watanabe e t a l (66) i l l u s t r a t e s r e s u l t s c h a r a c t e r i s t i c o f many s t u d i e s . These a u t h o r s suggest t h a t t h e e f f e c t s a r e r e l a t e d t o b i l e a c i d b i n d i n g c a p a c i t y and t h a t t h i s c o r r e l a t e s w i t h s e v e r i t y o f mucosal damage. Thus, the b i l e a c i d and f i b e r e f f e c t s may be m e c h a n i c a l r a t h e r t h a n because o f m e t a b o l i c a b e r r a t i o n s . In c o n t r a s t t o some o f t h e r e s u l t s r e f e r r e d t o above where i n c r e a s e d d i e t a r y f a t enhanced e x p e r i m e n t a l l y i n d u c e d c o l o n c a n c e r i n r a t s , we have f a i l e d t o o b s e r v e an e f f e c t o f e i t h e r q u a l i t y o r quant i t y o f f a t on i n d u c e d tumor i n c i d e n c e (67,68). T a b l e XV l i s t s r e s u l t s o f s t u d i e s w i t h t h r e e d i f f e r e n t f a t s and two d i f f e r e n t c o l o n c a r c i n o g e n s . The n e g a t i v e n a t u r e o f t h e s e two c a r e f u l l y conducted


172

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

s t u d i e s , one o f which (DMH) has been r e p e a t e d w i t h s i m i l a r r e s u l t s , c a s t s doubt on t h e s i g n i f i c a n c e o f d i e t a r y f a t on c o l o n c a r c i n o g e n e sis. The c o n f l i c t i n g d a t a between e p i d e m i o l o g i c a l and e x p e r i m e n t a l s t u d i e s might be e x p l a i n e d i n a number o f ways. Most l o g i c a l would be the d i v e r s i t y o f exposures o f humans t o e n v i r o n m e n t a l f a c t o r s , compared t o a s i n g l e v a r i a b l e i n a n i m a l s t u d i e s .


T a b l e XIV.

D i e t a r y F i b e r and C o l o n Cancer i n Rats Induced by Two Carcinogens C a r c i n o g e n and Tumor I n c i d e n c e (%) Azoxymethanol Methylnitrosourea F i b e r (15% o f D i e t ) (AOM) (NMU) Control 69.0 57.7 Alfalfa 83.3 53.3 Pectin 58.6 10.0 Bran 60.0 33.0 From Watanabe e_t a l . , 1979, a b r i d g e d . Q u a l i t y and Q u a n t i t y o f D i e t a r y F a t and C o l o n C a r c i n o G e n e s i s W i t h Two C o l o n C a r c i n o g e n s Dietary Fat Carcinogen/% C o l o n Tumors % (Wt) Type NMU DMH 5 Mixed 55 77 68 63 24 Beef T a l l o w 55 24 Corn O i l 63 38 24 Crisco 55 From Nauss e t a l . , 1983; 1984, a b r i d g e d . Each group comprised o f 40 r a t s e a c h . T a b l e XV.

L i p o t r o p e s and

Colon

Cancer

W h i l e t h e r e a r e no e p i d e m i o l o g i c d a t a a v a i l a b l e on l i p o t r o p i c f a c t o r s and c o l o n c a n c e r i n human p o p u l a t i o n s , r e s u l t s o f a n i m a l s t u d i e s suggest a p o s s i b l e r o l e f o r t h i s c l a s s o f n u t r i e n t s ( c h o l i n e , m e t h i o n i n e , v i t a m i n B-^ ^ d f o l a t e ) i n c o l o n c a r c i n o g e n e s i s ( 6 9 ) . Table XVI l i s t s r e s u l t s t y p i c a l o f t h o s e o b s e r v e d when r a t s a r e f e d a d i e t h i g h i n f a t , low i n l i p o t r o p e s and exposed t o a c o l o n c a r c i n o g e n . The l i p o t r o p i c a g e n t s a r e i n t i m a t e l y i n v o l v e d w i t h m e t h y l a t i o n and i t i s perhaps through t h i s mechanism t h a t t h e y e x e r t t h e i r e f f e c t s . Abe r r a n t m e t h y l a t i o n o f n u c l e i c a c i d s and a r e l a t i o n t o c a r c i n o g e n e s i s under a v a r i e t y o f c o n d i t i o n s , i s c u r r e n t l y under i n t e n s i v e i n v e s t i g a t i o n i n s e v e r a l l a b o r a t o r i e s (70,71).

Rat C o l o n Tumors Induced by DMH No. o f Rats With Tumors/TumorColon Dimethylhydrazine B e a r i n g Rat Carcinoma, % Dose , mg/kg Diet 2.0 86 Control 300 3.7 100 High-Fat 300 1.1 56 Control 150 2.6 85 High-Fat 150 From Rogers and Newberne, 1975, a b r i d g e d . Table

XVI.

D i e t a r y F a t and


13.

NEWBERNE

V i t a m i n A and

Esophageal and Colon Chemical Carcinogenesis Colon

173

Cancer


There i s l i t t l e i n the l i t e r a t u r e r e l a t i v e t o v i t a m i n A and c o l o n c a n c e r i n human p o p u l a t i o n s . E x p e r i m e n t a l animal s t u d i e s , however, s t r o n g l y suggest t h a t v i t a m i n A d e f i c i e n c y may have a r o l e i n t h i s type o f c a n c e r . We have shown t h a t a d e f i c i e n c y o f v i t a m i n A i n c r e a s e d DMH-induced tumors and s h o r t e n e d the l a g time f o r i n d u c t i o n , compared t o n o r m a l l y supplemented c o n t r o l s ( 7 2 ) . More r e c e n t l y (73) we have c o n f i r m e d a p r o t e c t i v e r o l e f o r v i t a m i n A i n c o l o n c a r c i n o genesis (Table XVII). F u r t h e r m o r e , we have shown (74) t h a t v i t a m i n A d e f i c i e n c y can r e s u l t i n c o l o n tumors i n r a t s g i v e n a f l a t o x i n B^ (AFB^) which i s n o r m a l l y a l i v e r c a r c i n o g e n ( T a b l e X V I I I ) . The c o l o n tumors a s s o c i a t e d w i t h the h e p a t o c a r c i n o g e n AFB.. appear t o be a r e s u l t o f d i f f e r e n c e s i n m e t a b o l i s m and b i n d i n g o f AFB^ o r i t s metabol i t e ^ ) t o c o l o n DNA under c o n d i t i o n s o f v i t a m i n A d e f i c i e n c y ( 7 5 ) .

Table XVII.

E f f e c t s o f 1 3 - c i s R e t i n o i c A c i d on DMH-Induced Tumors i n The Rat No. A n i m a l s Average No. No. A n i m a l s With Colon % With Tumors/ Treatment At R i s k Tumors Tumors Animal 3.1 C o n t r o l D i e t 3.0 yg 100 20 20 R e t i n y l Acetate 2.3 C o n t r o l D i e t 3.0 yg 8 40 20 R e t i n y l Acetate + 67 ug/g 1 3 - c i s Retinoic Acid From Newberne and Suphakarn, 1977.

Table XVIII.

V i t a m i n A S t a t u s , A f l a t o x i n B , and J. Tumors i n R a t s

Dietary Retinyl No. Acetate Rats at Risk Sex AFB, (ug/g) 1 Control M 0 24 3.0 F 0 26 3.0 + 24 M 3.0 + F 24 3.0 Low M 10 0.3 0 12 F 0 0.3 + M 66 0.3 + 42 F 0.3 High M 0 23 30.0 F 20 0 30.0 M + 26 30.0 + F 31 30.0 From Newberne and R o g e r s , 1976.

n

L i v e r and

Tumor I n c i d e n c e Colon Liver

(%) Both

0.0 0.0 87.5 79.1

0.0 0.0 4.1 8.3

0.0 0.0 4.1 8.3

0.0 0.0 89.4 76.2

0.0 0.0 28.8 28.6

0.0 0.0 25.7 11.9

0.0 0 92.3 83.9

0 0 7.7 9.7

0 0 7.7 6.4


Colon

174

XENOBIOTIC METABOLISM: NUTRITIONAL EFFECTS

Literature Cited 1. 2. 3. 4. 5. 6. 7.


8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.

"Diet, Nutrition and Cancer," National Academy of Sciences, 1982, p. 17-1. Doll, R. Brit J. Cancer 1969, 23, 1-8. Chilvers, C.; Fraser, P.; Beral, V. J. Epidemiol. Community Health 1979, 33, 127-133. Lipworth, L.L.; Rice, C.A. Cancer 1979, 43, 1927-1933. Tuyns, A.J.; Pequignot, G.; Abbatucci, J.S. Int. J. Cancer 1979, 23, 443-447. Keller, A.Z. Prev. Med. 1980, 9, 607-612. Pottern, L.M.; Morris, L.E.; Blot, W.J.; Zeigler, R.G.; Fraumeni, Jr., J.F. J. Natl. Cancer Inst. 1981, 67, 777-783. Schmidt, W.; Popham, R.E. Cancer 1981, 47, 1031-1041 Williams, R.R.; Horm, J.W. J. Natl. Cancer Inst. 1977, 58, 525547. Mettlin, C.; Graham, S.; Priore, R.; Marshall, J.; Swanson, M. Nutr. Cancer 1980, 2, 143-147. Bradshaw, E.; Schonland, M. Br. J. Cancer 1974, 30, 157-163. Gatei, D.G.; Odhiambo, P.A.; Orinda, D.A.O.; Muruka, F.J.; Wasuma, A. Cancer Res. 1978, 38, 303-307. Yang, C.S. Cancer Res. 1980, 40, 2633-2644. Hormozdiari, H.; Day, N.E.; Aramesh, B.; Mahboubi, E. Cancer Res. 1975, 35, 3493-3498. Joint Iran-IARC Study Group. J. Natl. Cancer Inst. 1977, 59, 1127-1138. Marasas, W.F.O.; Van Rensburg, S.J.; Mirocha, C.J. J. Agric. Food Chem. 1979, 27, 1108-1112. Lin, H.J.; Chan, W.C.; Fong, Y.Y.; Newberne, P.M. Nutr. Rpts. Internat. 1977, 15, 635-643. Fong, L.Y.Y.; Sivak, A.; Newberne, P.M. J. Natl. Cancer Inst. 1978, 61, 145-150. Gabrial, G.N.; Schrager, T.F.; Newberne, P.M. J. Natl. Cancer Inst. 1982, 68, 785-789. Newberne, P.M.; Schrager, T.F. Environmental Health Perspectives 1983, 50, 71-83. Russell, R.M. Am. J. Clin. Nutr. 1980, 33, 2741-2745. Mobarhan, S.; Russell, R.M.; Newberne, P.M.; Ahmed, S.B. Nutr. Rpts. Internat. 1984, 29, 639-645. Ahmed, S.B.; Russell, R.M. J. Lab. Clin. Med. 1982, 100, 211217. Fong, L.Y.Y.; Lee, J.S.K.; Chan, W.C.; Newberne, P.M. In Bartsch, H.; Castegnaro, M.; O'Neill, I.K.; Okada, M., Eds.; IARC SCIENTIFIC PUBLICATIONS No. 41, 1982, pp. 679-683. Fong, L.Y.Y.; Lee, J.S.K.; Chan, W.C.; Newberne, P.M. J. Natl. Cancer Inst. 1984, 72, 419-425. Magee, P.N.; Montesano, R.; Preussmann, R. In "Chemical Carcinogens"; Searle, C.E., Ed.; ACS Monograph No. 173, American Chemical Society: Washington, D.C., 1976. Fong, L.Y.Y.; Ng, W.L.; Newberne, P.M. In "N-Nitroso Compounds"; IARC PROCEEDINGS: Banff, Canada, 1983. Fong, L.Y.Y.; Ng, W.L.; Newberne, P.M. Cancer Letters, 1984, in press.


a13. NEWBERNE 29. 30. 31. 32.


33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57.

Esophageal and Colon Chemical Carcinogenesis 175

Chandra, R.K.; Newberne, P.M. In "Nutrition, Immunity and Infection: Mechanisms of Interactions"; Chandra, R.K.; Newberne, P.M., Eds.; Raven Press: New York, 1977; p. 246. Greene, H. In "Textbook of Pediatric Nutrition"; Suskind, R.M., Ed.; Raven Press: New York, 1981; pp. 119-120. Newberne, P.M. In "The Toxicologist"; The Society of Toxicology: Akron, 1984. Miller, J.A.; Miller, E.C. Advances in Cancer Res. 1953, 1, 339-396. Armstrong, B.; Doll, R. Internat. J. Cancer 1975, 15, 617-631. Wynder, E.L. Cancer Res. 1975, 35, 3388-3394. Lui, K.; Moss, D.; Persky, V.; Staniler, J.; Garside, D.; Soltero, I. Lancet 1979, 2, 782-785. Berg, J.W.; Howell, M.A. Cancer 1974, 34, 804-814. Howell, M.A. J. Chronic Disease 1975, 28, 67-80. Enstrom, J.E. Brit. J. Cancer 1975, 32, 432-439. Bingham, S.; Williams, D.R.R.; Cole, T.J.; James, W.P.T. Br. J. Cancer 1979, 40, 456-463. Malhotra, S.L. Med. Hypotheses 1977, 3, 122-126. MacLennan, R.; Jensen, O.M.; Mosbech, J.; Vuori, H. Am. J. Clin. Nutr. 1978, 31, 5239-5242. Jansson, B.; Jacobs, M.M.; Griffin, A.C. Adv. Exp. Med. Biol. 1978, 91, 305-322. Schrauzer, G.N.; White, D.A.; Schneider, C.J. Bioinorg. Chem. 1977a, 7, 23-34. Schrauzer, G.N.; White, D.A.; Schneider, C.J. Bioinorg. Chem. 1977b, 7, 35-36. Birt, D.F.; Lawson, T.A.; Julius, A.D.; Runice, C.E.; Salmasi, S. Cancer Res. 1982, 42, 4455-4459. Phillips, R.L.; Kuzma, J.W.; Lotz, T.M. In Banbury Report No. 4, Cold Spring Harbor Lab: New York, 1980a. Phillips, R.L.; Kuzma, J.W.; Beeson, W.L.; Lotz, T. Am. J. Epidemiol. 1980b, 112, 296-314. Phillips, R.L.; Snowdon, D.A. Cancer Res. (Suppl.) 1983, 43, 2403s-2408s. Lyon, J.L.; Sorenson, A.W. Am. J. Clin. Nutr. 1978, 31, 52275230. Lyon, J.L.; Gardner, J.W.; West, D.W.; Mahoney, A.M. Cancer Res. (Suppl.) 1983, 43, 2392s-2396s. Kolonel, L.N.; Abraham, M.Y.; Nomura, M.; Ward, H.; Hirohata, T.; Hankin, J.H.; Lee, J. Cancer Res. (Suppl.) 1983, 43, 2397s2402s. Reddy, B.S.; Hedges, A.R.; Laakso, K.; Wynder, E.L. Cancer 1978, 42, 2832-2838. Reddy, B.S.; Sharma, C.; Darby, L.; Laakso, K.; Wynder, E.L. Mutation Res. 1980, 72, 511-522. Reddy, B.S.; Weisburger, J.H.; Wynder, E.L. J. Natl. Cancer Inst. 1974, 52, 507-511. Reddy, B.S.; Watanabe, K.; Weisburger, J.H. Cancer Res. 1977, 37, 4156-4159. Reddy, B.S. Advances Nutr. Res. 1979, 2, 199-218. Reddy, B.S.; Mangat, S.; Sheinfil, A.; Weisburger, J.H.; Wynder E.L. Cancer Res. 1977, 37, 2132-2137.


176 58. 59. 60. 61. 62. 63. 64.


65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75.

XENOBIOTIC METABOLISM: NUTRITIONAL EFFECTS

Kritchevsky, D. In "Molecular Interrelations of Nutrition and Cancer"; Arnott, M.S.; VanEys, J.; Yang, Y.M.; Eds.; Raven Press: New York, 1982; pp. 209-217. Phillips, R.L. Cancer Res. 1975, 35, 3513-3522. Lyon, J.L.; Klauber, M.R.; Gardner, J.W.; Smart, C.R. N. Eng. J. Med. 1976, 294, 129-133. Barbolt, T.A.; Abraham, R. Proc. Soc. Exp. Biol. Med. 1978, 157, 656-659. Freeman, H.J.; Spiller, G.A.; Kim, Y.S. Cancer Res. 1980, 40, 2661-2665. Story, J.A.; Kritchevsky, D. J. Nutr. 1976, 106, 1292-1294. Nigro, N.D.; Bhadrachari, N.; Chomchai, C. Dis. Colon Rectum 1973, 16, 438-443. Doll, R.; Peto, R. J. Natl. Cancer Inst. 1981, 66, 1191-1308. Watanabe, E.; Reddy, B.S.; Weisburger, J.H.; Kritchevsky, D. J. Natl. Cancer Inst. 1979, 63, 141-145. Nauss, K.M.; Locniskar, M.; Newberne, P.M. Cancer Res. 1983, 43, 4083-4090. Nauss, K.M.; Locniskar, M.; Sondergaard ,D.; Newberne, P.M. Carcinogenesis 1984, 5, 225-260. Rogers, A.E.; Newberne, P.M. Cancer Res. 1975, 35, 3427-3431. Newberne, P.M.; deCamargo, J.L.V.; Clark, A.J. Toxicologic Path. 1982, 10, 95-109. Bosan, W.S.; Shank, R.C. Tox. and Appl. Pharm. 1983, 70, 324334. Rogers, A.E.; Herndon, B.J.; Newberne, P.M. Cancer Res. 1973, 33, 1003-1009. Newberne, P.M.; Suphakarn, V. Cancer 1977, 40, 2553-2556. Newberne, P.M.; Rogers, A.E. In "Fundamentals in Cancer Prevention"; Magee, P.N.; Takayama, S.; Sugimura, T.; Matsushima, T., Eds.; Tokyo University Press: Tokyo, 1976; pp. 15-40. Suphakarn, V.; Newberne, P.M.; Goldman, M. Nutrition and Cancer 1983, 5, 41-50.

RECEIVED January 23, 1985


Dietary Factors Affecting Biological Responses to ... - ACS Publications

Recommend Documents