376

Letters

to

date clearly favour the fat tion theory.

the Editor

theory rather than the fibre-deple-

Surgical Unit, Rayne Institute, University College Hospital Medical School, London WC1E

DIETARY FIBRE AND EXPERIMENTAL COLON CANCER

SIR,-We thank Dr Newcombe, Dr Thorne, Dr Lowenfels, and Mr Crofts (Jan. 13 issue), and others who have written, for their interest in our paper’ and have the following comments to make in reply. (1) Several correspondents incorrectly assume that the intention of our paper was to test Burkitt’s hypothesis linking intra-alimentary carcinogen concentration with colon carcinoma. This was not so, for nowhere in the paper do we mention fscal bulk or transit-time or even allude to such concepts. The object of the experiment was to test a specific scientific hypothesis (stated on p. 1278 of our paper), based on Burkitt’s general theory linking fibre depletion and colonic cancer. The primary interest of the study was not in the carcinogen itself, but in a possible modifying role for dietary fibre, related to its indirect effects on bile salt,2 cholesterol,3 and fat4 metabolism. We agree with criticisms of the use of a colon-cancer model induced by subcutaneously injected dimethylhydrazine for the purpose of studying mechanisms related to luminal carcinogen concentration, and hence did not use it for this purpose. (2) Some correspondents criticise our statistical analysis, suggesting that different conclusions might have been reached from our data had the results been analysed at an arbitrary point in time (e.g., 37 or 38 weeks). We have already presented our argument against the arbitrary sacrifice method of experimental evaluation.5 Dr Lowenfels uses an inappropriate statistical test (see Peto6 for reasons) to derive a "nearly significant" result from our data. (3) The "excessive" dosage of carcinogen used has been criticised by those who argue that no protective effect would be observable at such a dosage. This is not so. The fibre experiment was part of a larger study, designed to test, as separate independent variables, the relative strengths of various dietary modifiers (fibre, cholesterol, and bile salts) of dimethylhydrazine carcinogenesis. In a parallel experiment,’ conducted simultaneously and using the identical carcinogen dosage, 30% of a group of rats fed a fibre and cholesterol free diet (’Vivonex’) failed to develop colonic carcinoma at all, dying from incidental causes near the end of the study. In addition, the animals on vivonex showed a highly significant prolongation of the time to tumour presentation and survival. Clearly, this high carcinogen dosage can be protected against by dietary manipulation alone. Furthermore, the experiment demonstrated that the protective effort of vivonex was due, in part, to its lack of cholesterol. The conclusion of these two experiments was that a cholesterol-free diet was a more powerful dietary modifier of dimethylhydrazine carcinogenesis than was added dietary fibre in the form of bran. Finally, we would agree with Mr Burkitt8 and others that human colon cancer is likely to have a multifactorial aetiology. The salient pathogenetic factors appear to be associated with the fat and/or fibre components of the diet. Dietary fat and fibre are complexly interrelated, and our experimental work attempts to disentangle the relative contributions of these components to the pathogenesis of colonic cancer. The results to .

1. Cruse, J. P., Lewin, M. R., Clark, C. G. Lancet, 1978, ii, 1278. 2. Pomare, E. W., Heaton, K. W. Br. med. J. 1973, ii, 262. 3. Trowell, H. C. Am. J. clin. Nutr. 1972, 25, 464. 4. Hill, M. J. Digestion, 1974, 11, 289. 5. Cruse, J. P., Lewin, M. R., Clark, C. G. Lancet, 1978, ii, 843. 6. Peto, R. Br. J. Cancer, 1974, 29, 101. 7. Cruse, J. P., Lewin, M. R., Ferulano, G. P., Clark, C. G. Nature, 822. 8. Burkitt, D. P. Personal communication, 1979.

PETER CRUSE MICHAEL LEWIN CHARLES CLARK

6JJ

ŒSTROGENS, PROSTAGLANDINS, AND CERVICAL RIPENING

correspondence on oestrogen and prostapretreatment of the unfavourable cervix before induction of labour deserves further comment. Thiery et al.1 have questioned the efficacy of the oestradiol pretreatment proposed by Gordon and Calder.2 Further controlled clinical trials are needed to resolve this aspect of the discussion. Prostaglandins have been used to ripen the cervix.3 There are, however, considerable changes in uterine activity after P.G. administraction,4 and Gordon and Calder suggested that oestrogens are preferable due to the relative lack of uterine stimulation with the low doses (150 mg oestradiol valerate) they used. Craft and Yovichs report that higher doses (300 mg) can cause sufficient uterine contractions to establish labour within 24 h. The main point of dispute is the mechanism by which low-dose oestrogen pretreatment ripens the cervix. Hillier and Wallis6 suggest that a "direct effect of the hormone on the cervix might be to delay softening", and in support of this suggestion cite in-vitro work demonstrating œstradiol inhibition of hydroxyproline release from explants of non-pregnant human cervix. They further suggest, presumably by exclusion of the possibility of a local action, that "changes in the cervix induced by oestradiol result mainly from induced contractility". Unless cervical ripening can be explained by increased collagen catabolism, the results cited cannot be viewed in this context. Although there are reports of decreased hydroxyproline concentration in both the human and ovine cervix8 at term there are no firm data on total collagen content. These data are required as evidence for increased collagen breakdown as an active biochemical mechanism underlying the ripening process. The ovine cervix increases considerably in size during pregnancy,9 and the decreased collagen concentrations (measured by hydroxyproline) may well represent "dilution" of the tissue collagen rather than breakdown. The inhibitory action of oestradiol on uterine involution10 is almost certainly via an action on collagenase since the major involve-11 ment of this enzyme in this process has been demonstrated." The data of Hillier and Wallis6 may represent a similar action of oestradiol on collagenase, but a role for this enzyme in cervical ripening is yet to be defined. The recently reported dramatic effects of oestradiol on the ovine cervix were observed without an effect on uterine activity.l2 We believe that a local action of oestradiol may be explained through an indirect mechanism involving P.G.S. Stimulation of P.G. synthesis in uterine tissues by oestrogens is documented.13 Recent data from our laboratory have shown an SIR,- The

recent

glandin (P.G.)

1. Thiery, M., and others Lancet, 1978, ii, 835. Gordon, A. J., Calder, A. A. ibid. 1977, ii, 1319. Calder, A. A., Hillier, K., Embrey, M. P. in Advances in Prostaglandin and Thromboxane Research (edited by B. Samuelsson and R. Paoletti); vol II.

2. 3.

New York, 1976. 4. Calder, A. A., Embrey, M. P., Tait, T. Br. J. Obstet. Gynœc 1977, 84, 264. 5. Craft, T., Yovich, J. Lancet, 1978, ii, 208. 6. Hillier, K., Wallis, R. ibid. 1978, ii, 1377. 7. Danforth, D. N., Buckingham, J. C., Roddick, J. W. Am. J. Obstet. Gynec

1960, 80, 939. Ward, W. R. PH.D thesis, University of Liverpool, 1968. 9. Abusineina, M. E. Br. Vet. J. 1969, 125, 21. 10. Woessner, J. F., Jr. Biochem J. 1979, 112, 637. 11. Jeffrey, J. J., Gross, J. Biochemistry, 1970, 9, 268. 12. Munro, C. D., Calder, A. A., Fleming, R., McManus, T. J., Aughey, B., McPhee, G., Hillier, K., Coutts, J. R. T. Paper presented to the Society 8.

1978, 276,

for the Study of Fertility Dec. 13, 1978. 13. Liggins, G. C., Fairclough, R. J., Grieves, B. S. Rec. Prog. Horm Res.

1973, 29,

111.

S. A., Kendall, J. Z., Knox,

Dietary fibre and experimental colon cancer.

376 Letters to date clearly favour the fat tion theory. the Editor theory rather than the fibre-deple- Surgical Unit, Rayne Institute, Universit...
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