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Cancer research
Cancer
research
295
dimethylnitrosamine (DMNA) and diethanolamine (DEA). The tests were again carried out in male rats, which were fed a semi-purified diet for 12 days, fasted for 6 hr, given a single oral dose of the test compound and then killed 18 hr later. Serum analyses of ten enzymes, 19 amino acids and urea were performed terminally and livers were studied by light and electron microscopy. Sorbitol dehydrogenase was found to be the most sensitive of the enzyme indicators studied, showing an increase in activity with a dose of 9.4 mg TA/kg or 5.1 mg DMNA/kg. Increased activities of seven other enzymes (isocitric dehydrogenase, fructose-l-phosphate aldolase, glutamic-oxalacetic and glutamic-pyruvic transaminases, ornithine-carbamoyl transferase and malic and lactic dehydrogenases) were recorded with higher doses of these two compounds. A dose of 800 mg DEA/kg increased the activity of six of these enzymes, but ornithine-carbamoyl transferase and lactic dehydrogenase were only affected by 1600mg DEA/kg, a dose which also induced glutamic dehydrogenase and fructose-1,6phosphate aldolase. Activities of several enzymes were dose-dependent. Serum levels of arginine were decreased by 25.4, 13.7 and 800 mg/kg doses of TA, DMNA and DEA, respectively, and in the first two cases ornithine levels were increased. DEA at 800mg/kg had a variable effect on ornithine, but increased the serum levels of urea. Morphological changes were detectable at dosage levels below those required to affect serum enzyme levels, evidence of histological damage being present in at least some of the animals treated with 3.5 mg TA/kg, 1.9 mg DMNA/kg and 200 mg DEA/kg. Nevertheless, serum-enzyme studies have obvious practical advantages over biopsy or autopsy, and the data presented here support the conclusion of the earlier study, suggesting that sorbitoldehydrogenase activities, which were dose-dependent over a wide range of doses of each test chemical, offer the best chance of detecting minimal hepatic damage.
CANCER
RESEARCH
2834. Calculi, alkaline urine and bladder tumours Flaks, Antonia, Hamilton, J. M. & Clayson, D. B. (1973). Effect of ammonium chloride on incidence of bladder tumours induced by 4-ethylsulfonylnaphthalene-l-sulfonamide. J. mtn. Cancer Inst. 51, 2007. The importance of contact with urine and of the presence of calculi as factors in the development of tumours in bladders implanted with paraffin-wax pellets has been demonstrated in the rat (Cited in F.C.T 1974, 12, 592). The study cited above was designed to show whether the incidence of bladder tumours induced in mice by 4-ethylsulphonylnaphthalene-1-sulphonamide (ENS) could be altered by changing the pH of the urine and thus affecting the formation of calculi. Prolonged dietary administration of ENS to mice results in the production of an alkaline urine, the formation of bladder calculi, the development of a marked degree of hyperplasia of the bladder epithelium and frequently the induction of bladder tumours. When mice were given 1% ammonium chloride (NH&l) in their drinking-water as well as 0.01% ENS in the diet, the pH of the urine was kept almost within the normal range (5.67.2 compared with 55-6.7 in the controls), After treatment for 52 wk these mice showed some
296
Cancer
research
mild hyperplasia of the bladder epithelium but were free of both bladder turnout-s and calculi. After a comparable period, the group of 26 mice treated only with ENS included 18 with moderate or severe epithelial hyperplasia, 13 with bladder calculi, seven with bladder tumours and 14 with hydronephrosis. The range of urinary pH in this group was 6.9-9.0. In two of these mice there was no correlation between the presence of calculi and tumour formation. These results are in accord with previous evidence that the presence of calculi may play an important role in bladder-tumour induction in rodents. They also support an earlier suggestion that the bladder changes induced by ENS are largely due to rises in urinary pH and irritation from calculi rather than to the direct action of the chemical on the bladder epithelium.
research
295
dimethylnitrosamine (DMNA) and diethanolamine (DEA). The tests were again carried out in male rats, which were fed a semi-purified diet for 12 days, fasted for 6 hr, given a single oral dose of the test compound and then killed 18 hr later. Serum analyses of ten enzymes, 19 amino acids and urea were performed terminally and livers were studied by light and electron microscopy. Sorbitol dehydrogenase was found to be the most sensitive of the enzyme indicators studied, showing an increase in activity with a dose of 9.4 mg TA/kg or 5.1 mg DMNA/kg. Increased activities of seven other enzymes (isocitric dehydrogenase, fructose-l-phosphate aldolase, glutamic-oxalacetic and glutamic-pyruvic transaminases, ornithine-carbamoyl transferase and malic and lactic dehydrogenases) were recorded with higher doses of these two compounds. A dose of 800 mg DEA/kg increased the activity of six of these enzymes, but ornithine-carbamoyl transferase and lactic dehydrogenase were only affected by 1600mg DEA/kg, a dose which also induced glutamic dehydrogenase and fructose-1,6phosphate aldolase. Activities of several enzymes were dose-dependent. Serum levels of arginine were decreased by 25.4, 13.7 and 800 mg/kg doses of TA, DMNA and DEA, respectively, and in the first two cases ornithine levels were increased. DEA at 800mg/kg had a variable effect on ornithine, but increased the serum levels of urea. Morphological changes were detectable at dosage levels below those required to affect serum enzyme levels, evidence of histological damage being present in at least some of the animals treated with 3.5 mg TA/kg, 1.9 mg DMNA/kg and 200 mg DEA/kg. Nevertheless, serum-enzyme studies have obvious practical advantages over biopsy or autopsy, and the data presented here support the conclusion of the earlier study, suggesting that sorbitoldehydrogenase activities, which were dose-dependent over a wide range of doses of each test chemical, offer the best chance of detecting minimal hepatic damage.
CANCER
RESEARCH
2834. Calculi, alkaline urine and bladder tumours Flaks, Antonia, Hamilton, J. M. & Clayson, D. B. (1973). Effect of ammonium chloride on incidence of bladder tumours induced by 4-ethylsulfonylnaphthalene-l-sulfonamide. J. mtn. Cancer Inst. 51, 2007. The importance of contact with urine and of the presence of calculi as factors in the development of tumours in bladders implanted with paraffin-wax pellets has been demonstrated in the rat (Cited in F.C.T 1974, 12, 592). The study cited above was designed to show whether the incidence of bladder tumours induced in mice by 4-ethylsulphonylnaphthalene-1-sulphonamide (ENS) could be altered by changing the pH of the urine and thus affecting the formation of calculi. Prolonged dietary administration of ENS to mice results in the production of an alkaline urine, the formation of bladder calculi, the development of a marked degree of hyperplasia of the bladder epithelium and frequently the induction of bladder tumours. When mice were given 1% ammonium chloride (NH&l) in their drinking-water as well as 0.01% ENS in the diet, the pH of the urine was kept almost within the normal range (5.67.2 compared with 55-6.7 in the controls), After treatment for 52 wk these mice showed some
296
Cancer
research
mild hyperplasia of the bladder epithelium but were free of both bladder turnout-s and calculi. After a comparable period, the group of 26 mice treated only with ENS included 18 with moderate or severe epithelial hyperplasia, 13 with bladder calculi, seven with bladder tumours and 14 with hydronephrosis. The range of urinary pH in this group was 6.9-9.0. In two of these mice there was no correlation between the presence of calculi and tumour formation. These results are in accord with previous evidence that the presence of calculi may play an important role in bladder-tumour induction in rodents. They also support an earlier suggestion that the bladder changes induced by ENS are largely due to rises in urinary pH and irritation from calculi rather than to the direct action of the chemical on the bladder epithelium.