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2357. Thoughts on colon carcinogenesis
440
CANCER RESEARCH
CANCER RESEARCH
2356. Are triphenylmethane dyes carcinogenic? Rosenkranz, H. S. & Cart, H. S. (1971). Possible hazard in use of gentian violet. Br. reed. J. 3, 702. Triphenylmethane dyes have long been used in topical applications for controlling bacterial and fungal infections of the skin. No adverse effects apart from the occasional appearance of contact sensitization, have hitherto been reported in clinical practice. Evidence is now offered that gentian violet (GV), crystal violet (CV), methyl violet (MV) and malachite green (MG) are capable of interaction with the DNA of living ceils and so may induce abnormalities of cell division. This interaction was demonstrated by a procedure based on the fact that cells deficient in DNA polymerase are less capable of countering the inhibitory effect of agents that react with DNA than are cells well supplied with this enzyme. Two strains of Escherichia coli, the second being a DNA polymerase-deficient mutant of the first, were exposed to a number of agents, including compounds known not to react with cellular DNA (colistin, kanamycin, neomycin, streptomycin and ampicillin), known carcinogens (methyl methanesulphonate, N-methyl-N-nitrosouretharte and nitrosofluorene), the four dyes (GV, CV, MV and MG) and acridine orange (AO), which has been reported to have some carcinogenic effect in animals (Cited in F.C.T. 1970, 8, 474). Both strains of the organism were equally sensitive to the antibiotics, but the mutant strain was significantly more sensitive to the known carcinogens, to AO and to the four triphenylmethane dyes, especially GV. Claiming that this experimental procedure appears to be reliable in detecting mutagens and carcinogens, the authors conclude from these findings that the clinical use of triphenylmethane dyes should be carefully scrutinized and re-evaluated. 2357. Thoughts on colon carcinogenesis Burkitt, D. P. (1971). Epidemiology of cancer of the colon and rectum. Cancel" 28, 3. Weisburger, J. H. (1971). Colon carcinogens: Their metabolism and mode of action. Cancer 28, 60. Cancer of the colon is the second most common cancer found in the western world today. The two papers cited above are both concerned with this relatively new and important problem although they approach it from somewhat different angles. In the first paper, a well-known cancer epidemiologist discusses the significance of the tenfold difference in bowel-cancer incidence between those living in the industrialized western communities and the inhabitants of the more remote areas of Africa and Japan. Of particular interest in this context is the fact that descendants of emigrant Africans and Japanese who moved to the USA are as susceptible to bowel cancer as the local Americans, so that the incidence of the disease in these people is now as high as in their neighbours. Furthermore, bowel cancer and several other related conditions, including diverticula, adenomatous polyps, appendicitis, ulcerative colitis and haemorrhoids, follow a similar geographical distribution and what is more these other non-infectious diseases have all at some time in the past been shown to be associated with colon carcinogenesis. Burkitt's hypothesis (loc. cit.) is that these differences in bowel-cancer incidence can be accounted for by variations in dietary habits, the lack of unabsorbable fibre and excess of refined carbohydrate in the western diet predisposing to bowel cancer. His argument states that changes in
CANCER RESEARCH
441
the cellulose content of the food alter colonic activity, intestinal transit times and the bulk and consistency of stools, while excess carbohydrate alters the bacterial content of the faeces. The result is that, with western diets, bile salts and food constituents are retained in the colon for prolonged periods during which the action of the intestinal flora can convert certain materials to potentially carcinogenic compounds. In a study involving the ingestion of radio-opaque pellets by English and African schoolboys, the author has been able to show that the intestinal transit time and the bulk, texture and odour of the stools are clearly related to the fibre content of the diet--the less fibre eaten, the longer the transit time and the smaller, harder and more foetid the stools. As it is well known that bowel cancer develops in the area of the intestine where such material would collect, this is valuable evidence in favour of Burkitt's theory; normally of course tumours in the epithelial lining of body canals are extremely rare, the environmentally-abused bronchi being the only other common site for such developments. Given that material is being retained longer in the colon and that it is therefore being exposed to the perhaps somewhat altered intestinal flora for more prolonged periods, it remains to be shown that carcinogens can be produced under these circumstances. This was one of the aims of the second paper cited above, which is a review of the structure and metabolism of chemicals known to be carcinogenic to the colon. Two groups of compounds are recognized as being in this category, namely derivatives of 3-methyl-4-aminobiphenyl and of 1,2-dimethylhydrazine, the latter including cycasin and methylazoxymethanol (MAM). All require the action of the gut flora before becoming actively carcinogenic. 3-Methyl-4-aminobiphenyl derivatives, for instance, are absorbed in the upper reaches of the gut and are known to be first N-hydroxylated and then conjugated with glucuronic acid in the liver. The conjugate is excreted in the bile, from which the intestinal bacteria liberate the free N-hydroxy compound, the postulated active carcinogen. 1,2-Dimethylhydrazine is metabolized similarly, forming the glucuronide of azoxymethanol, which is converted to the highly carcinogenic MAM by the gut flora. The conversion of cycasin to MAM on the other hand does not involve absorption, the compound passing straight into the colon, where it is enzymatically split to MAM. Clearly, there is considerable if circumstantial evidence in favour of Burkitt's theory; it still remains to be shown, however, whether the carcinogens mentioned above or their derivatives are in fact ingested to any significant degree by populations in the western countries afflicted by a high incidence of colonic cancer.
CANCER RESEARCH
CANCER RESEARCH
2356. Are triphenylmethane dyes carcinogenic? Rosenkranz, H. S. & Cart, H. S. (1971). Possible hazard in use of gentian violet. Br. reed. J. 3, 702. Triphenylmethane dyes have long been used in topical applications for controlling bacterial and fungal infections of the skin. No adverse effects apart from the occasional appearance of contact sensitization, have hitherto been reported in clinical practice. Evidence is now offered that gentian violet (GV), crystal violet (CV), methyl violet (MV) and malachite green (MG) are capable of interaction with the DNA of living ceils and so may induce abnormalities of cell division. This interaction was demonstrated by a procedure based on the fact that cells deficient in DNA polymerase are less capable of countering the inhibitory effect of agents that react with DNA than are cells well supplied with this enzyme. Two strains of Escherichia coli, the second being a DNA polymerase-deficient mutant of the first, were exposed to a number of agents, including compounds known not to react with cellular DNA (colistin, kanamycin, neomycin, streptomycin and ampicillin), known carcinogens (methyl methanesulphonate, N-methyl-N-nitrosouretharte and nitrosofluorene), the four dyes (GV, CV, MV and MG) and acridine orange (AO), which has been reported to have some carcinogenic effect in animals (Cited in F.C.T. 1970, 8, 474). Both strains of the organism were equally sensitive to the antibiotics, but the mutant strain was significantly more sensitive to the known carcinogens, to AO and to the four triphenylmethane dyes, especially GV. Claiming that this experimental procedure appears to be reliable in detecting mutagens and carcinogens, the authors conclude from these findings that the clinical use of triphenylmethane dyes should be carefully scrutinized and re-evaluated. 2357. Thoughts on colon carcinogenesis Burkitt, D. P. (1971). Epidemiology of cancer of the colon and rectum. Cancel" 28, 3. Weisburger, J. H. (1971). Colon carcinogens: Their metabolism and mode of action. Cancer 28, 60. Cancer of the colon is the second most common cancer found in the western world today. The two papers cited above are both concerned with this relatively new and important problem although they approach it from somewhat different angles. In the first paper, a well-known cancer epidemiologist discusses the significance of the tenfold difference in bowel-cancer incidence between those living in the industrialized western communities and the inhabitants of the more remote areas of Africa and Japan. Of particular interest in this context is the fact that descendants of emigrant Africans and Japanese who moved to the USA are as susceptible to bowel cancer as the local Americans, so that the incidence of the disease in these people is now as high as in their neighbours. Furthermore, bowel cancer and several other related conditions, including diverticula, adenomatous polyps, appendicitis, ulcerative colitis and haemorrhoids, follow a similar geographical distribution and what is more these other non-infectious diseases have all at some time in the past been shown to be associated with colon carcinogenesis. Burkitt's hypothesis (loc. cit.) is that these differences in bowel-cancer incidence can be accounted for by variations in dietary habits, the lack of unabsorbable fibre and excess of refined carbohydrate in the western diet predisposing to bowel cancer. His argument states that changes in
CANCER RESEARCH
441
the cellulose content of the food alter colonic activity, intestinal transit times and the bulk and consistency of stools, while excess carbohydrate alters the bacterial content of the faeces. The result is that, with western diets, bile salts and food constituents are retained in the colon for prolonged periods during which the action of the intestinal flora can convert certain materials to potentially carcinogenic compounds. In a study involving the ingestion of radio-opaque pellets by English and African schoolboys, the author has been able to show that the intestinal transit time and the bulk, texture and odour of the stools are clearly related to the fibre content of the diet--the less fibre eaten, the longer the transit time and the smaller, harder and more foetid the stools. As it is well known that bowel cancer develops in the area of the intestine where such material would collect, this is valuable evidence in favour of Burkitt's theory; normally of course tumours in the epithelial lining of body canals are extremely rare, the environmentally-abused bronchi being the only other common site for such developments. Given that material is being retained longer in the colon and that it is therefore being exposed to the perhaps somewhat altered intestinal flora for more prolonged periods, it remains to be shown that carcinogens can be produced under these circumstances. This was one of the aims of the second paper cited above, which is a review of the structure and metabolism of chemicals known to be carcinogenic to the colon. Two groups of compounds are recognized as being in this category, namely derivatives of 3-methyl-4-aminobiphenyl and of 1,2-dimethylhydrazine, the latter including cycasin and methylazoxymethanol (MAM). All require the action of the gut flora before becoming actively carcinogenic. 3-Methyl-4-aminobiphenyl derivatives, for instance, are absorbed in the upper reaches of the gut and are known to be first N-hydroxylated and then conjugated with glucuronic acid in the liver. The conjugate is excreted in the bile, from which the intestinal bacteria liberate the free N-hydroxy compound, the postulated active carcinogen. 1,2-Dimethylhydrazine is metabolized similarly, forming the glucuronide of azoxymethanol, which is converted to the highly carcinogenic MAM by the gut flora. The conversion of cycasin to MAM on the other hand does not involve absorption, the compound passing straight into the colon, where it is enzymatically split to MAM. Clearly, there is considerable if circumstantial evidence in favour of Burkitt's theory; it still remains to be shown, however, whether the carcinogens mentioned above or their derivatives are in fact ingested to any significant degree by populations in the western countries afflicted by a high incidence of colonic cancer.