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ABSTRACT1,2-dimethylhydrazine (DMH), administered weekly to mice for 20 weeks, induces tumors in the distal segment of colon. Tumors are preceded by enlargement of the mucosal glands resulting from increases in the number of total cells and 3H-thymidine labeled celldcrypt. Cells located in the crypt base normally undergo 2-3 divisions as they migrate toward the lumen, and they become post-mitotic in the upper crypt. It is not known if cells in these enlarged crypts have rates of turnover similar to cells in normal crypts. Groups of w/s female mice were treated with DMH (20 mg/kg body wt) for 3,8, or 16 weeks; controls were given 0.001 M EDTA. After treatment, the animals were injected with 3H-thymidine and killed one hour or 1,2,4,7 or 17 days later. Autoradiographs were prepared from sections of distal colon. The total cells/crypt column in 30 cryptdanimals were counted. Crypts were divided into 10 equal segments based on the crypt length and the labeled cells/segment were counted. The relative number of labeled cells and the distribution of these cells within crypts were similar in DMH-treated and control animals after one hour. However, as the cells migrated toward the lumen, the number of labeled cells doubled after 2 days and tripled after 4 days in DMH-treated animals but only doubled during the 4 days in controls. This difference was caused by retention of an increased number of dividing cells in the lower 4 segments of the crypts and suggests an increase in those cells that divide twice. In addition, increased numbers of labeled cells were retained in the upper 3 segments of DMH-treated animals after 4 days. These findings indicate that the crypt cells of DMH-treated animals are generally more immature than those of controls and this immaturity contributes to the enlargement of mucosal glands during carcinogenesis.
ABSTRACT1,2-dimethylhydrazine (DMH), administered weekly to mice for 20 weeks, induces tumors in the distal segment of colon. Tumors are preceded by enlargement of the mucosal glands resulting from increases in the number of total cells and 3H-thymidine labeled celldcrypt. Cells located in the crypt base normally undergo 2-3 divisions as they migrate toward the lumen, and they become post-mitotic in the upper crypt. It is not known if cells in these enlarged crypts have rates of turnover similar to cells in normal crypts. Groups of w/s female mice were treated with DMH (20 mg/kg body wt) for 3,8, or 16 weeks; controls were given 0.001 M EDTA. After treatment, the animals were injected with 3H-thymidine and killed one hour or 1,2,4,7 or 17 days later. Autoradiographs were prepared from sections of distal colon. The total cells/crypt column in 30 cryptdanimals were counted. Crypts were divided into 10 equal segments based on the crypt length and the labeled cells/segment were counted. The relative number of labeled cells and the distribution of these cells within crypts were similar in DMH-treated and control animals after one hour. However, as the cells migrated toward the lumen, the number of labeled cells doubled after 2 days and tripled after 4 days in DMH-treated animals but only doubled during the 4 days in controls. This difference was caused by retention of an increased number of dividing cells in the lower 4 segments of the crypts and suggests an increase in those cells that divide twice. In addition, increased numbers of labeled cells were retained in the upper 3 segments of DMH-treated animals after 4 days. These findings indicate that the crypt cells of DMH-treated animals are generally more immature than those of controls and this immaturity contributes to the enlargement of mucosal glands during carcinogenesis.
The effect of duodenogastric reflux on cell proliferation and mucosal mass in the stomach was studied. Male Wistar rats (n = 118) were submitted to Polya partial gastrectomy, partial gastrectomy with Roux-en-Y diversion of bile, total duodenogastric reflux or handling of the stomach alone (sham operation). Following oral administration of the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine for 6 months, animals were killed 6, 9 or 12 months postoperatively and their stomachs were examined for crypt cell production rate and mucosal DNA content. Compared with shams, crypt cell production rate was more than twice as high in the gastric remnant 12 months after Polya partial gastrectomy (P less than 0.001) and median DNA content was 31 per cent greater (P = 0.05). After total duodenogastric reflux, DNA content was 62 per cent greater than in shams (P = 0.02), while Roux-en-Y diversion reduced crypt cell production rate by 65 per cent (P less than 0.001). Only Polya gastrectomy increased the number of rats developing gastric carcinomas (9 versus 2 shams; P less than 0.05). Increased mucosal cell proliferation in rats with duodenogastric reflux may help to explain the development of gastric stump cancer.
Bile salts appear to be important promoters of colon carcinogenesis. This study was designed to assess the importance of the fecal stream in cholic acid-induced colon tumor promotion. Male Sprague-Dawley rats underwent transverse colostomy after induction with dimethylhydrazine (DMH) and the excluded distal colon was irrigated with saline or sodium cholate (23 microM) 5 times per week until sacrifice. Controls initially injected with saline were similarly treated. All surviving animals were sacrificed at 28 weeks after the last DMH injection. Five animals from each group were randomly chosen to assess tritiated thymidine labeling and distribution by autoradiography in normal appearing colon mucosa of irrigated bowel. Cholate irrigation failed to increase tumor yield or modify the proportion of adenomas and adenocarcinomas in this model. Paradoxically, fewer tumors per affected rat were noted with sodium cholate irrigation. Cholate irrigation also failed to affect crypt cellularity, thymidine labeling indices, and labeling distribution in DMH-treated rats and controls. An effect of DMH was seen, however, with an increase in thymidine labeling index and increased labeling in the top half of the crypt in all DMH-treated groups. This study suggests that tumor promotion with primary bile salts is not a direct affect and may result from further bile salt metabolism within the fecal stream. DMH-induced changes in cell proliferation were reproduced with this model. Use of an excluded colon segment to assess the effect of suspected tumor promoters on carcinogenesis or colon mucosal cell proliferation is feasible and may be a useful model for future studies.
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