The Inhibition and Promotion of Cancers by Folic Acid, Vitamin B

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VICTOR HERBERT Hahnemann University, Philadelphia, PA 19102 For the past two years, our group has been collaborating with that of Dr. Ludwik Gross in the area of these studies, attempting to "switch off" the oncogene for guinea pig leukemia/lymphoma (1). The concept involved is that DNA methylation, and specifically methylation of cytosine in higher eukaryotes can directly suppress gene expression. This concept has been elaborated in several reviews, of which the most recent is by Eick et al. (2) in Analytical Biochemistry 135:165-171, 1983. The first dramatic presentation of possible clinical value of being able to demethylate a gene was the study by Heller and his associates in Chicago suggesting that they could "switch on" the fetal hemoglobin gene using 5-azacytidine, presumably by hypomethylating the fetal globin gene. They collaborated with Ley et al. in a study strongly suggesting that they could, in fact, switch on fetal hemoglobin synthesis with 5-azacytidine (3). This was confirmed by Charache and Dover and their associates at Johns Hopkins University (4) but Nathan and Lethvin and their associates showed that two other S-phase specific cytotoxic agents, hydroxyurea and cytosine arabinoside, could also increase fetal hemoglobin synthesis, Stanatiannopoulos and Poppianopoulou found that cytosine arabinoside can produce identical response in baboons to 5-azacytidine, and Nathan was quoted as concluding that the three drugs "probably act in the same way. Methylation has nothing to do with it" (5). However, W. French Anderson and his associates were able to show directly in the cell culture system that 5-azacytidine does in fact selectively hypomethylate fetal globin genes, but that other genes, including an oncogene, are remethylated shortly after losing their methyl groups. These superficially divergent results can be reconciled by the concept that hypomethylation causes the persistent hemoglobin, whereas other mechanisms produce the acute increased production of fetal hemoglobin which occurs after 5-azacytidine (or hydroxyurea or cytosine arabinoside (5). Similarly, different acute and persistent effects may explain 0097-6156/85/0277-0031 $06.00/0 © 1985 American Chemical Society

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

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why the same antifolate, methotrexate, which can shut down a lympho-proliferative malignancy, may result years later in the development of a second malignancy (1). One can speculate that an acute toxic effect kills the tumor but that the same methotrexate which acutely toxically kills the tumor, in a long period of time will result in demethylation of an oncogene, which can then be expressed as second malignancy. Other evidence that demethylation can cause the expression of malignancies comes from studies by Feinberg and Vogelstein at Johns Hopkins (6) at the Institute Pasteur by Bourgeois and her associates, who found that glucocorticoids can cause expression of murine mammary tumor virus (MMTV) by glucocorticoid-induced methylation of long-terminal repeat sequences (7). Similarly, Proirier and his associates published a number of studies delineating the ability of methyl-deficient, amino acid-defined diets to produce liver tumors in rats treated both with and without initiating doses of diethylnitrosamine (8, 9). Their studies indicate that diethylmethyl deficiency markedly promotes liver carcinogenesis and exhibits complete carcinogenetic activity in this organ in the rat. Rogers and Newberne had shown that dietary methyl deficiency enhances the activities of a number of hepatocarcinogens, and Shinizuka and Lombardi have found that choline deficiency enhanced the hepatocarcinogenic activities of several agents. The concept that deficiency of folate or vitamin B-12, or any other cause of failure to methylate DNA and/or RNA can activate malignancy by hypomethylation or oncogenes, and that methylating oncogenes can inhibit malignancy by making them dormant, is similar to the concept of "relaxed control" of RNA synthesis. In the f50s, Mendel and Borek (10) had noted that when an organism autotrophic from methionine is deprived of methionine, it loses its ability to suppress synthesis of RNA, which is then synthesized more rapidly. It was speculated that deficiency of B-12 or folate could produce similar "relaxed control". It is possible that some forms of vitamin B-12 and of folic acid may act as inhibitors of methylation and other forms as promoters of methylation of RNA and DNA (1). Reduced forms of folic acid are metabolically active; oxidized forms may be antimetabolites (1). Hydroxocobalamin is metabolically active; cyanocobalamin can be a B-12 antimetabolite (1). Leuchtenberger et al. had reported that inositol Inhibited animal tumor growth but various B vitamins did not (11, 12). This requires reinvestigation to determine whether inositol can methylate oncogenes. Oxidized folate monoglutamate, which is not a metabolically active form of the vitamin, not only did not inhibit spontaneous breast cancer in mice but actually produced a more rapid growth of the primary tumors and a significant increase in lung metastases. This work requires repeating today, particularly from the point of view of whether metabolically

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

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Inhibition and

Promotion of Cancers

i n a c t i v e f o l a t e , t h a t i s , o x i d i z e d f o l a t e , can promote tumor development but m e t a b o l i c a l l y a c t i v e f o l a t e , p a r t i c u l a r l y the v e r y a c t i v e t r i g l u t a m a t e s , can promote m e t h y l a t i o n of oncogenes and t h e r e b y i n h i b i t t h e i r e x p r e s s i o n . F o r many y e a r s , a number of workers have been e x p l o r i n g the q u e s t i o n of whether one form of a v i t a m i n can be a growth promoter by a c t i n g as a coenzyme ( i . e . , a promoter of normal and tumor c e l l growth) w h i l e a n o t h e r form of the same v i t a m i n c a n a t t a c h t o the same apoenzyme or o t h e r l i g a n d ( s u c h as a v i t a m i n t r a n s p o r t i n g p r o t e i n ) and t h e n jam the machinery, j u s t as a key w i t h a t o o t h m i s s i n g can f i t i n t o a l o c k and t h e n not t u r n . The answer t o that question i s c l e a r l y yes. S l i g h t t o major d i f f e r e n c e s i n the same v i t a m i n s t r u c t u r e ( i . e . , a n a l o g u e s and congeners) b o t h e x i s t i n n a t u r e and a r e s y n t h e s i z a b l e ; some of them a r e a n t a g o n i s t s o r a n t i - v i t a m i n s which can be c r e a t e d from v i t a m i n s by o n l y s l i g h t l y warping t h e i r s t r u c t u r e ( 1 ) . F a r b e r et a l . (13) r e p o r t e d from H a r v a r d g i v i n g p t e r o y l t r i g l u t a m i c a c i d ( t e r o p t e r i n ) and p t e r o y l d i g l u t a m i c a c i d ( d i o p t e r i n ) , b o t h s y n t h e s i z e d by U. SubbaRow and h i s a s s o c i a t e s a t L e d e r l e L a b o r a t o r i e s , t o 90 p a t i e n t s w i t h v a r i o u s malignancies, noting that " i n general, adult p a t i e n t s experienced improvement i n energy, a p p e t i t e , sense of w e l l being...might be a s c r i b e d t o improved morale r e s u l t i n g from f r e q u e n t v i s i t s , more m e d i c a l a t t e n t i o n . . . " They a l s o r e p o r t e d i n c o n s t a n t temporary d e c r e a s e s i n s i z e of m e t a s t a s e s i n some tumors and d e g e n e r a t i o n and n e c r o s i s i n o t h e r s . The a p o c r y p h a l s t o r y i s t h a t Dr. F a r b e r was a l s o g i v i n g f o l i c a c i d ( t h e o x i d i z e d , s t a b l e p h a r m a c e u t i c a l form of the v i t a m i n ) t o c h i l d r e n with l y m p h o p r o l i f e r a t i v e malignancies (lymphocytic leukemia and lymphoma) u n t i l one of h i s r e s i d e n t s c o l l e c t e d s u f f i c i e n t d a t a t o suggest t h a t the c h i l d r e n r e c e i v i n g t h i s new v i t a m i n were d y i n g f a s t e r t h a n t h o s e c h i l d r e n not r e c e i v i n g i t . T h i s o b s e r v a t i o n a l l e g e d l y l e d Dr. F a r b e r t o ask the L e d e r l e p e o p l e t o c r e a t e a warped f o l i c a c i d m o l e c u l e which would i n t e r f e r e w i t h f o l a t e metabolism i n the m a l i g n a n t c e l l s , and t h i s was done by a d d i n g an NH2 group, t h e r e b y c r e a t i n g a m i n o p t e r i n . A second a l t e r a t i o n , m e t y h y l a t i o n i n the 1 0 - p o s i t i o n , c r e a t e d m e t h o t r e x a t e , s t i l l one of our most p o t e n t a n t i - c a n c e r a g e n t s , p a r t i c u l a r l y e f f e c t i v e against childhood lymphoproliferative d i s o r d e r s and t r o p h o b l a s t i c m a l i g n a n c i e s . There i s c o n s i d e r a b l e e v i d e n c e t h a t r a p i d l y growing n e o p l a s t i c t i s s u e consumes f o l a t e a t so r a p i d a r a t e t h a t f o l a t e d e f i c i e n c y m e g a l o b l a s t o s i s can o c c u r i n the h o s t c e l l s (14, 1 5 ) . There i s a l s o e v i d e n c e t h a t v i t a m i n B-12 d e f i c i e n c y may slow tumor growth, whether t h a t d e f i c i e n c y r e s u l t s f r o m i n a d e q u a t e a b s o r p t i o n o r e l e v a t e d l e v e l s i n serum of a v i t a m i n B-12 binder which does not d e l i v e r the v i t a m i n t o tumor t i s s u e ( 1 6 ) , but w i l l d e l i v e r i t t o the l i v e r i n a calcium-dependent f a s h i o n (14, 17-20). I n t e r e s t i n g l y , g r a n u l o c y t e s and l i v e r a r e a major s o u r c e

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

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of serum b i n d i n g p r o t e i n s f o r b o t h b i t a m i n B-12 and f o l i c a c i d (21), and m a l i g n a n c i e s o f g r a n u l o c y t e s and l i v e r may p a r t l y c o n t r o l themselves by r e l e a s i n g i n t o t h e serum l a r g e amounts o f b i n d e r s f o r v i t a m i n B-12 and f o l i c a c i d which b i n d t h o s e v i t a m i n s and t h e r e b y p r e v e n t d e l i v e r y t o , and nourishment o f , t h e tumor. O x i d i z e d f o l a t e i s not o n l y m e t a b o l i c a l l y dead buyt may even be n e u r o t o x i c . F o r example, a p a t i e n t w i t h e p i l e p s y who has not had a c o n v u l s i o n i n y e a r s because d i l a n t i n has produced complete c o n t r o l , c a n be thrown i n t o an immediate c o n v u l s i o n w i t h a megadose of f o l i c a c i d , because f o l i c a c i d and d i l a n t i n compete f o r a b s o r p t i o n a t the b r a i n c e l l s u r f a c e , and t o o much o x i d i z e d f o l i c a c i d w i l l b l o c k the a b i l i t y of the b r a i n c e l l t o t a k e up d i l a n t i n , s i m i l a r t o t h e c o m p e t i t i o n between d i l a n t i n and f o l i c a c i d f o r uptake by the g u t c e l l ( 2 2 ) . There appear t o be one-way t r a n s p o r t systems t o remove o x i d i z e d f o l a t e s from the nervous system (22, 23) and t o remove v i t a m i n B-12 analogues from t h e body v i a the b i l e ( 2 4 ) . Some of the B-12 analogues p r e s e n t i n m u l t i v i t a m i n / m i n e r a l p r e p a r a t i o n s may b l o c k mammalian c e l l metabolism (25) and s i n c e they b l o c k normal c e l l metabolism, p o s s i b l y may UTbck m a l i g n a n t c e l l metabolism. F o r a number of y e a r s , R u s s i a n workers have been f e e d i n g analogues of v i t a m i n B-12 t o normal and m a l i g n a n t c e l l s and showing t h a t t h e s e analogues w i l l knock out B-12 metabolism (25a). Do the B-12 analogues (which have now been found i n human serum, l i v e r , b i l e r e d c e l l s , and b r a i n ) (26) p l a y any r o l e i n the p r o m o t i o n o r i n h i b i t i o n of c a r c i n o g e n e s i s i n humans? Levels of analogue i n serum a r e e l e v a t e d i n some m a l i g n a n c i e s ( 1 ) . L e v e l s of m e t h y l a t e d bases i n u r i n e a r e e l e v a t e d i n some h e m a t o l o g i c m e l i g n a n c i e s ( J L ) . I n t h e same h e m a t o l o g i c a l m a l i g n a n c i e s i n which m e t h y l a t e d bases a r e e l e v a t e d i n the u r i n e , B-12 analogue i s e l e v a t e d i n t h e b l o o d serum ( 1 ) . We have r e c e n t l y found enormous q u a n t i t i e s of a n a l o g u e s i n human s t o o l , and have been s t u d y i n g whether t h e analogue i n human c o l o n b a c t e r i a i s the s o u r c e of t h e analogue i n human t i s s u e s ( 2 7 ) . I n p r e l i m i n a r y s t u d i e s , we found two l a r g e analogue peaks i n human b i l e and two s i m i l a r l a r g e analogue peaks i n human s t o o l . We a r e now a t t e m p t i n g t o f i n d out whether t h e s e peaks a r e t h e same analogue ( 2 7 ) . I f they a r e , t h e n the analogue i n b i l e would have come from t h e analogue i n s t o o l , because t h e q u a n t i t y o f analogue p r e s e n t i n f o o d i s t i n y compared t o the q u a n t i t y p r e s e n t i n human stool. Working w i t h Dr. Ludwik G r o s s i n our f i r s t attempts t o m e t h y l a t e oncogenes, we gave 5 - m e t h y l c y t i d i n e (5mC) t o g u i n e a p i g s i n whom was t r a n s p l a n t e d g u i n e a p i g leukemia/lymphoma ( 1 ) • The e x p e r i m e n t s o v e r a six-month p e r i o d were u n s u c c e s s f u l i n showing any d r a m a t i c i n h i b i t i o n , a l t h o u g h t h e r e was a non-statistically significant inhibition. We s u b s e q u e n t l y began g i v i n g 5 - i o d o c y t i d i n e (5IC) t o t h e s e g u i n e a p i g s , h a v i n g s w i t c h e d from 5MC because of the e v i d e n c e t h a t t h e m e t h y l group i s t a k e n

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

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Inhibition and Promotion of Cancers

off on passage through the liver, resulting in cytidine alone being incorporated into the DNA and RNA of the oncogene. We though that perhaps iodine would not be removed from the cytidine as easily, and iodocytidine would be Incorporated intact into RNA, with the iodine perceived by the cell as if it were a methyl group, as is true for iododeoxyuridine being perceived by cells as if it were methyldeoxyuridine (i.e., thymidine) (1). These studies are not yet completed; preliminary results have been equivocal but teasing. Evidence that methylation can suppress normal and malignant gene expression, and demethylation can bring about expression, continues to build (28-30), although expression is not always related to state of methylation (31, 32). Literature Cited 1. Herbert, V. In "Nutritional Factors in the Induction and Maintenance of Malignancy"; Butterworth, C.E., and Hutchinson, M.L., Eds.; Academic Press: New York, 1983, pp. 273-287. 2. Eick, D., Fritz, H.-J., Doerfler, W.: Analyt. Biochem. 1983, 135, 165-171. 3. Ley, T.J., DeSimone, J., Noguchi, C.T., Turner, P. H., Schechter, A.N., Heller, P., Nienhuis, A.W., Blood 1983, 62, 370-380. 4. Charache, S., Dover, G., Smith, K., Talbot, C., Conover, C., Jr., Moyer, M., Boyer, S. Proc. Natl. Acad. Sci. 1983, 80, 4842-6. 5. Kolata, G. Science 1984, 223, 470-1. 6. Feinberg, A.P., Vogelstein, B. Nature 1983, 301, 89. 7. Mermod, J.-J., Bourgeois, S., Defer, N., Crepin, M. Proc. Natl. Acad. Sci. 1983, 80, 110-114. 8. Brown, J.D., Wilson, M.J., Poirier, L.A. Carcinogenesis 1983, 4, 173-177. 9. Mikol, Y.B., Hoover, K.L., Creasia, D., Poirier, L.A. Carcinogenesis 1983, 4. 10. Mandel, L.R., Borek, E. Biochem. Biophys. Res. Comm. 1961,

6, 138. 11. Leuchtenberger, C., Leuchtenberger, R., Laszlo, D., Lewisohn, R. Science 1945, 101, 46. 12. Leuchtenberger, C., Leuchtenberger, R. In: "Nutritional Factors in the Induction and Maintenance of Malignancy"; Butterworth, C.E., and Hutchinson, M.L., Eds.; Academic Press: New York, 1983, pp. 131-148. 13. Farber, S., Cutler, E.C., Hawkins, J.W., Harrison, J.H., Peirce, E.C., Lenz, G.G. Science 1947, 106, 619-621. 14. Herbert, V. "The Megaloblastic Anemias." Grune and Stratton, New York, 1959.

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36 15.

Chanaran, I. "The Megalblastic Anemias." Blackwell Scientific, St. Louis, 1979. 16. Corcino, J., Zalusky, R., Greenberg, M., Herbert, V. Brit. J. Haemat. 1971, 20, 511-520. 17. Herbert, V. J. Clin. Invest. 1958, 37, 646-650. 18. Herbert, V., Spaet, T.H. Amer. J. Physiol. 1958, 195, 194-196. 19. Allen, R.H. Prog. Hemat. 1975, 9, 57. 20. Beck, W.S. In: "B-12"; Dolphin, D., Ed. John Wiley and Sons: New York, 1982, pp 21. Herbert, V., Colman, N. In "Lithium Effects on Granulopoiesis and Immune Function"; Rossof, A.H., Robinson, W.A., Eds. Plenum Publishing: New York, 1980, pp. 61-78. 22. Colman, N., Herbert, V. In: "Biochemistry of Brain"; Kumar, S., Ed. Pergamon Press: New York, 1980, pp. 103, 125. 23. Poncz, M., Colman, N., Herbert, V., Schwartz, E., Cohen, A.R. J. Ped. 1981, 98, 76-79. 24. Kanazawa, S., Herbert, V. Trans. Assoc. Amer. Phys. 1984, 96, 336-344. 25. Kondo, H., Binder, M.J., Kolhouse, J.F., Smythe, W.R., Podell, E.R., Allen, R.H. J. Clin. Invest. 1982,k 70, 889-898. 25a. Myashcheva, N.W., Quadros, E.V., Matthews, D.M., Linnell, J.C. Biochim. Biophys. Acta 1979, 588, 81-88. 26. Kanazawa, S., Herbert, V. Clin. Res. 1982, 30, 540A. 27. Herbert, V., Drivas, G., Manusselis, C., Mackler, B., Eng, J., Schwarts, E. Trans. Assoc. Amer. Phys. 1984, 97. 28. Wilson, V.L., Jones, P.A. Cell 1983, 32, 239-246. 29. Christman, J.K., Mendolsohn, N., Herzog, D., Schneiderman, N. Cander Res. 1983, 43, 763-769. 30. Harrison, J.J., Anisowicz, A., Gadi, I.K., Raffeld, M., Sager, R. Proc. Natl. Acad. Sci. 1983, 80, 6606-66.0. 31. Gautsch, J.W., Wilson, M.C. Nature 1983, 301, 32-37. 32. Graessman, M., Graessmann, A., Wagner, H., Werner, E., Simon, D. Proc. Natl. Acad* Sci. 1983, 80, 6470-6474. RECEIVED January

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