593

SECONDARY AMYLOIDOSIS AND ANTIOXIDANTS

SIR,-In response to your May 27 editorial I should like todraw attention to the possible role of antioxidants in the pre-vention and treatment of secondary amyloidosis. Ethoxyquin(’Santoquin’), a quinoline derivative almost completely pre-vented spontaneous amyloidosis in male LAFl mice;’ butylatedhydroxytoluene (BHT) was less effective.l.2 The two antioxi-dants also inhibited development of amyloidosis when added tothe diet of casein injected C3HeB/FeJ male mice;3 a similareffect was found with ethoxyquin in CBA/J mice.4Plasma electrophoretic studies of the casein injected

C3HeB/FeJ mice showed3 that ethoxyquin, and to a lesserextent BHT, depressed the appearance of a protein fraction inthe ofj-glycoprotein region; recent studies5.6 suggest that thisxl-glycoprotein fraction was serum amyloid A (SAA). In-creased SAA values are always associated with increased cop-per levels" presumably due mainly to the oxidase caeruloplas-min" suggesting that tissue levels of free radical reactions areincreased. Since free-radical induced degradation of hyalur-onic acid can be inhibited by antioxidants8 we suggested3 thatthe unknown glycoprotein in the aI-glycoprotein area had beenmobilised from a component of the ground substance by oxida-tive removal of polysaccharide chains while the more exten-sively degraded material was precipitated. The extent to whichthis suggestion is correct is uncertain since recent studies claimthat SAA is produced by fibroblasts,9 neutrophils’O and hepa-tocytes ;" SAA may be a component of the microfilaments.12Aside from their possible stabilising effect on the ground

substance, antioxidants may also slow the development of amy-loidosis in some manner by ameliorating4 the depression of theimmune system4·’3 associated with this disorder; antioxidantsenhance both humoral and cell-mediated immune responses14and have a beneficial effect on T-suppressor cell function.15Although the details of the inhibiting action of antioxidants onamyloidosis remains to be clarified it is apparent that a free

1. Harman D. Free radical theory of aging: Effect of free radical inhibitors onthe life span of male LAF1 mice: second experiment. Gerontologist 1968;8 (no 3): 13 abstr.

2. Harman D. Free radical theory of aging: effect of free radical reactions in-hibitors on the mortality rate of male LAF1 mice. J Gerontal 1968; 23:476-82.

3. Harman D, Eddy DE, Noffsinger J. Free radical theory of aging: inhibitionof amyloidosis in mice by antioxidants; possible mechanism. J Am GeriatSoc 1976; 24: 203-10.

4. Cathcart ES, Yonkosky D, Harman D. Santoqum therapy in casein-inducedexperimental amyloidosis. 14th Int Congr Rheumatol (San Francisco).1977. abstr.

5. Linke RP, Sipe JD, Pollock PS, Ignoczek TF, Glenner GG. Isolation of alow molecular-weight serum component antigenically related to an amy-loid fibril protein of unknown origin. Proc Nat Acad Soc USA 1975; 72:1473-76.

6. Benson MD, Scheinberg MA, Shirahama T, Cathcart ES, Skinner M. Kine-tics of serum amyloid protein A in casein-induced murine amyloidosis. JClin Invest 1977; 59: 412-17.

7. Underwood EJ. Copper. In: Trace elements in human and animal nutrition,3rd ed. New York: Academic Press, 1971: 59-115.

8. Pigman W, Rizvi S, Holley HL. Depolymerization of hyaluronic acid by theORD reaction. Arthr Rheum 1961; 4: 240-52.

9. Linder E, Anders RF, Natvig JB. Connective tissue origin of the amyloid-related protein SAA. J Exp Med 1976; 144: 1336-46.

10. Rosenthal CJ, Sullivan L. Serum amyloid A: Evidence for its origin in poly-morphonuclear leukocytes. J Clin Invest 1978; 62: 1181-86.

11 Benson MD, Kleiner E. Synthesis and secretion of serum amyloid protein A(SAA) by hepatocytes in mice treated with casein. J Immunol 1980; 124:495-99.

12. Linder E, Lehto VP, Virtenen I, Stanman S, Natvig JP. Localization of amy-loid-related serum protein SAA-like material to intermediate (10nm) fila-ments of cultured human embryonal fibroblasts. J Exp Med 1977; 146:1158-63.

13. Clerici E, Garotta G, Parta C, Bigi G, Pessina A, Villa ML. Immunologicalaspects of amyloidosis. Israel J Med Sci 1973; 9: 881-87.

14. Harman D, Heidrick ML, Eddy DE. Free radical theory of aging: effect offree radical-reaction inhibitors on the immune response. J Am Geriat Soc1977; 25: 400-07.

15. Harman D. Free radical theory of aging: Beneficial effect of antioxidants onthe life span of male NZB mice; Role of free radical reactions in the deter-ioration of the immune system with age and in the pathogenesis of sys-temic lupus erythematosus. Age 1980; 3: 64-73.

radical(s) reaction is involved in pathogenesis and that this canbe inhibited by dietary antioxidants.The beneficial effect of dimethylsulphoxide on amyloidosis16

may, then, be related, at least in part, to the ability of thiscompound" to scavenge hydroxyl radicals. In the light ofLavie’s work on the degradation of amyloid fibrils18 it seemsreasonable to suggest that treatment of secondary amyloidosiswith antioxidants to inhibit the formation of new amyloidfibrils might result in a "cure" of this ubiquitous disorder.

Medical Center,University of Nebraska,Omaha, Nebraska 68105, U.S.A. DENHAM HARMAN

CANCER OF THE DIGESTIVE TRACT ANDMYCOTOXINS OF FUSARIUM SPECIES

SIR,-In an editorial on beer and bowel cancer’ you say:"The more the studies, however, the greater the confusion".This confusion is related to the fact that the significant agentsresponsible for the development of these tumours have notbeen recognised; the factors studied are of secondary impor-tance.

In an earlier editorial on oesophageal cancer2 you referred tomouldy grain, contaminated with toxigenic Fusarium sp.,which may be used for making alcoholic drinks. I havereviewed the relationship of Fusarium mycotoxins to disordersand tumours associated with alcoholic drinks.3 These commonfield fungi produce toxic metabolites (carcinogenic for thedigestive tract4) under specific conditions, including high mois-ture and low temperatures (5-200C). This may explain thegeographical and climatic variations in the incidence oftumours of the gastrointestinal tract, and of the oesophagus.The localisation of the tumours at a particular site of the

digestive tract depends on the dietary intake of vitamins,especially of those of the B group and vitamin A. At low intakeof these vitamins, the tumours caused by the ingested, directlyacting carcinogenic agents become localised near the site ofentry; they become shifted to sites and organs more remotefrom the route of entry, the higher the levels, in the respectivetissues, of B vitamins and of the coenzymes of which the Bvitamins are the essential moieties.

This is borne out by the observations in U.S.A., where theincidence of stomach cancer declined, but that of colorectaltumours increased, following the high dietary intake of meatand vitamins in recent times.One would expect that the high incidence of oesophageal

cancer among the Chinese in the Henan Provinces might shiftto cancer of the bowel with the increase in their standard of

living, were it not for the fact that the Chinese have recognisedthe hazards of mouldy foodstuffs, contaminated by fusaria,and are likely to take measures to eliminate this source of car-cinogens.

Department of Pathology,Royal Veterinary College,London NW1 0TU R. SCHOENTAL

16. Van Rijswijk MH, Donker Ab JM, Ruinen L. Dimethylsulphoxide in amyloi-dosis. Lancet 1979; i: 207-08.

17. Taniguchi H, Takagi H, Hatano H. Free-radical intermediates in the reac-tion of the hydroxyl radical with dialkyl sulfoxides. J Chem Phys Chem1972; 76: 135-38.

18. Lavie G, Zucker-Franklin D, Franklin EC. Degradation of serum amyloidA protein by surface-associated enzymes of human blood monocytes. JExp Med 1978; 148: 1020-31.

1. Editorial. Beer and bowel cancer. Lancet 1980; i: 1396-97.2. Editorial. Leads in oesophageal cancer. Lancet 1974; ii: 504.3. Schoental R. Relationships of Fusarium mycotoxins to disorders and

tumours associated with alcoholic drinks. Nutr Cancer (in press).4. Schoental R, Joffe AZ, Yagen B. Cardiovascular lesions and various tumours

found in rats given T-2 toxin, a tnchothecene metabolite of Fusarium.Cancer Res 1979; 39: 2179-89.

5. Lin P, Tang W. The epidemiology and etiology of esophageal cancer inChina. J Cancer Res Clin Oncol 1980; 96: 121-30.