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PubMed1989

[Effect of estradiol dipropionate on the development of uterine sarcoma induced by 1,2-dimethylhydrazine in mice].

The study was concerned with the influence of single dose of estradiol dipropionate on its promoting effect on 1,2-dimethylhydrazine-induced tumors in female CBA/CaLac mice. Estradiol dipropionate given within 19 weeks did not affect carcinogenesis whereas 39-week treatment stimulated uterine sarcoma development irrespective of single dose and schedule of administration.

1,2-Dimethylhydrazine↗
PubMed1986

Relationship between colonic luminal pH, cell proliferation, and colon carcinogenesis in 1,2-dimethylhydrazine treated rats fed high fiber diets.

The comparative effects of different fibers on colonic luminal pH, crypt cell proliferation, and colon carcinogenesis were studied in 120 male Sprague-Dawley rats. The animals were divided into five equal groups and fed either a basal fiber free diet or the basal diet supplemented with 10% pectin, cellulose or guar, or 20% oat bran for up to 30 weeks. 1,2-Dimethylhydrazine was given at 20 mg/kg body weight as a weekly s.c. injection for 12 weeks. Food intake and weight gain were similar in all diet groups. At sacrifice, in vivo pH measurements showed that compared to fiber free rats, all fibers significantly acidified large bowel luminal contents (P less than 0.05). In the guar group 62.5% of rats developed colonic tumors compared to 33.4% of the fiber free rats (P less than 0.05). The yield of proximal colonic adenocarcinomas in the oat bran, pectin, and guar groups was increased by 4.5 to 5 times over the fiber free level (P less than 0.05-0.025). Pectin and guar provided the greatest stimulus to cell proliferation. A lower luminal pH was associated with a higher tumor yield and increased epithelial cell proliferation. Thus, acidification of colonic contents by high fiber diets failed to inhibit rat colon carcinogenesis, while the consumption of soluble fibers, such as oat bran, pectin, and guar, was associated with enhancement of proximal colon carcinogenesis.

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PubMed1986

Postnatal carcinogenic study of 1,2-dimethylhydrazine dihydrochloride in rats.

The outbred SPF rats of the Ripb: Wist stock were applied subcutaneously 1,2-dimethylhydrazine dihydrochloride (DMHD) at a concentration of 0.036% and 0.144% from the first day of age after the birth. In nine experimental groups DMHD was administered for first 5, 10, 15 and 20 days of age after the birth at total doses of 0.36 to 2.16 mg. With the highest applied dose, all animals died during the treatment, further deaths were recorded in groups in which DMHD was administered for first 5 to 10 days. The maximum length of survival was one year. The conclusion of the study was achieved only by the control animals and by 36.6% of males and 13.8% of females of the experimental group. From the 24th week of age, hepatic and renal tumors were detected in rats. In the liver hepatocellular carcinomas and benign hepatomas occurred, and were found in all groups which had been applied DMHD, furthermore cholangiomas, mostly in the groups which had been applied DMHD up to the age of 15 days and cavernomas in the groups which had been applied DMHD up to the age of 20 days. Practically in all rats which had been administered DMHD focal preneoplastic hyperplasia of liver cells was detected. In the kidney always a mixed malignant mesenchymal tumor was found in all animals of the groups treated up to age of 15 days.

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PubMed1987

Organ-specific effects of 1,2-dimethylhydrazine in hamster.

Uptake and metabolism of the carcinogen 1,2-dimethylhydrazine (DMH) were compared in isolated epithelial cells from the colon and the small intestine. A new method was developed to separate colonic epithelial cells into surface columnar cells and crypt cells without the use of any proteolytic enzymes. Colonic columnar cell-enriched fraction exhibited DMH metabolism two to three times higher than that of crypt cells. The carcinogen binding was much lower in the small intestine as compared to the colon. In the small intestine, the crypt cell-enriched fraction showed higher carcinogen binding as compared to villus cells. Pyrazole was found to inhibit DMH binding by isolated small intestinal and colonic epithelial cells. The extent of inhibition was maximum in cells showing the greatest ability to incorporate DMH.

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PubMed1988

[Modifying effect of ascorbic acid and sodium ascorbate on uterine carcomogenesis induced by 1,2-dimethylhydrazine in CBA mice].

Administration of ascorbic acid (0.3% in drinking water) inhibited the promoting effect of estradiol dipropionate on the 1,2-dimethylhydrazine-induced uterine sarcomogenesis in CBA mice. However administration of sodium ascorbate intensified the promoting effect of estradiol on the uterine sarcomogenesis, as evidenced by the shortening of the periods of tumour incidence.

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PubMed1987

Distribution of laminin and collagen type IV in rat colon tumors induced by 1,2-dimethylhydrazine.

Immunofluorescent distribution of basement membrane components laminin and collagen type IV was studied in 51 rat colon tumors induced by 1, 2-dimethylhydrazine. In normal colonic mucosa, adenomas and carcinomas in situ continuous basement membranes were present, while in adenocarcinomas they were altered to different extents. An uncoordinated loss, or dissociation, of the two markers studied was found: the degree of collagen type IV loss was often much higher than that of laminin in the same tumor. These data suggest that a reliable determination of cancer invasion by monitoring basement membrane alteration requires the use of several basement membrane markers.

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PubMed1988

Carcinogenicity of deuterium-labeled 1,2-dimethylhydrazine in mice.

To study the effect of deuterium substitution on the carcinogenicity of 1,2-dimethylhydrazine (DMH) in mice, two comparisons were made between DMH and its fully methyl-deuterated analogue, [2H6]DMH. In a lifetime study with the CBA strain, groups of 19-30 animals of each sex were dosed s.c. weekly with 8 mg/kg of either DMH or [2H6]DMH for 8, 16, or 32 weeks. In the second study, female CF-1 mice were given DMH or [2H6]DMH in 10 weekly s.c. doses of 12 mg/kg each (13.2 mg/kg for [2H6]DMH) and examined for colon tumors 36 weeks after the first dose. Deuteration significantly decreased tumor incidence in the colon of males (P less than 0.01) and the anal tissue of both sexes (P less than 0.05) but increased that of hepatomas and lung tumors in males (P less than 0.01). Substrate deuteration did not significantly affect overall incidence of any other tumor type, however, including hemangioendotheliomas and kidney tumors in both sexes, as well as colon, uterine, ovarian, liver, and lung tumors in females. The results indicate that C--H bond breakage is kinetically important in the activation of DMH to its ultimately carcinogenic form in organs such as the male colon (relative risk in DMH-versus [2H6]DMH-treated animals approximately equal to 6), and that inhibition of this process by substrate deuteration allows a diversionary mechanism having a smaller isotope effect to become relatively more extensive. The qualitatively different effect in other organs (e.g., kidney, relative risk approximately equal to 1) supports recent suggestions that the net mechanism of activation can differ from one target tissue to another, possibly by striking a different balance between parallel metabolic pathways. The lack of a significant isotope effect on overall colon tumor incidence in females of either strain suggests that differences in relative importance among competing enzymes may also be responsible for sexual dimorphism in tumor induction by DMH.

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PubMed1986

Augmentation of 1,2-dimethylhydrazine-induced colon cancer by experimental colitis in mice: role of dietary vitamin E.

Because ulcerative colitis predisposes to colonic cancer, for determination of the effect of colitis on experimental colon carcinogenesis, rectal instillations of peptides that attract and activate neutrophils were used to induce colitis in CD-1 (ICR) BR mice receiving 20 weekly injections of the carcinogen 1,2-dimethylhydrazine [(DMH) CAS: 540-73-8]. From week 4 through week 15 of DMH injections, twice-weekly enemas of formyl-norleucyl-leucyl-phenylalanine were given to DMH-treated mice. The effect of the antioxidant vitamin E in the diet (1,750 IU/kg diet) was studied in another group of mice treated with DMH and having colitis. Four weeks after DMH was discontinued, cancer occurred in 9 of 28 (32%) animals with DMH plus control enemas, in 22 of 29 (76%) animals with DMH plus colitis (P = .001), and in 16 of 28 (57%) animals with DMH plus colitis plus supplemental vitamin E (P = .11 compared with the group with DMH and colitis). Colitis enhances DMH-induced colonic carcinogenesis.

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PubMed1987

1,2-Dimethylhydrazine-induced nuclear aberrations in A/J and C57BL/6J mouse colonic crypts.

A single exposure to 1,2-dimethylhydrazine [(DMH) CAS: 540-73-8] produces several forms of aberrant nuclei in the crypts of the murine colon. The frequency of nuclear aberrations (NAs) was examined in the distal colonic crypts in DMH-sensitive A/J mice and relatively DMH-resistant C57BL/6J mice before and after a single exposure to DMH. NAs, mitotic figures, and crypt column heights were scored for all animals as a function of time following administration of DMH. In both strains there was a significant increase in the absolute and relative frequency of NAs by 12 hours, with a corresponding drop and subsequent overshoot in the mitotic index by 48 hours after DMH. The temporal changes in crypt column height correlate closely with the temporal changes in frequency of NAs in both strains. The results showed that both inbred strains respond to acute DMH exposure in a similar and parallel fashion over time. It was concluded that the NA index assay is a sensitive method for detecting early DMH exposure. However, this assay does not relate to ultimate outcome after chronic DMH exposure and should not be used as a predictor of eventual neoplastic transformation of colonic mucosa with this carcinogen.

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PubMed1987

Qualitative and quantitative changes in sialomucins during 1,2-dimethylhydrazine-induced colon carcinogenesis in the rat.

Regional differences in goblet cell glycoproteins have been demonstrated qualitatively and, to a limited extent, quantitatively in the normal adult colon. In disease states, alterations in these glycoproteins, particularly the sialoglycoproteins (SGs), have been reported. The present study defined parallel qualitative and quantitative changes in SGs in three colon regions during 1,2-dimethylhydrazine [(DMH) CAS: 540-73-8]-induced carcinogenesis. SGs were assessed histochemically by use of high iron diamine-Alcian blue (pH 2.5) staining, and tissue sialic acid levels were measured by a modified Warren assay. Two groups of inbred SD rats (n = 28) were pair-fed nutritionally complete liquid diets with 36% of calories supplied as ethanol or isocaloric carbohydrates. The dietary alcohol was added to selectively enhance rectal tumors, a region of prevalent tumors in humans. Both groups received 4 weeks of liquid diet followed by 4 weeks of standard laboratory chow with weekly sc injections of DMH. This 8-week cycle was repeated four times (32 wk). Animals from each group were sacrificed at 8, 16, 24, and 32 weeks, and adjacent tissues from proximal and distal colon and rectum were prepared for histology and biochemical assay. The results showed a progressive increase in sialomucin staining in normal-appearing mucosa in distal colon and rectum in both groups but not in the proximal colon. In contrast, tissue sialic acid increased in all three regions as early as 8 weeks, and significant increases were consistently present by 32 weeks. A different pattern was observed in tissue from frank tumors. Compared with normal-appearing mucosa, both sialomucin staining and tissue sialic acid levels were reduced in tumor tissue by 32 weeks. These studies indicated that tissue sialic acid levels may provide a simple and reliable screening technique in the early diagnosis of premalignant change in all regions of the colon.

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PubMedDate not supplied

The influence of physical activity in 1,2 dimethylhydrazine induced colon carcinogenesis in the rat.

Recent epidemiologic findings indicate that relative risk of colon cancer is augmented with increasing proportion of time spent on sedentary occupations, and reduced with occupations requiring high levels of work-related physical activity. Therefore, the influence of exercise on experimental colon carcinogenesis was investigated. Spontaneous running wheel activity was related to incidence of 1,2 dimethylhydrazine (DMH) colon tumor induction. Colon tumor incidence was significantly reduced in animals that were allowed spontaneous wheel activity throughout the period of DMH tumor induction vs standard housed controls (p less than 0.05), indicating that, in the rat, physical activity protects against colon tumorigenesis. Further comparisons reveal a mild positive association (p = 0.07) between activity and incidence of tumors in the left colon. These results are in accord with epidemiologic findings indicating reduced colon cancer risk with increased physical activity. Possible mechanisms for the protective influence of physical activity on tumorigenesis include reduction in fecal pH, body weight and increased antioxidant enzyme activity. To the extent that epidemiologic associations between colon cancer and activity are inclusive of the multidimensional nature of physical activity, animal models such as that utilized in this experiment can be utilized for investigating the etiologic potential, or strength of association in variables that have been epidemiologically associated with colon cancer risk.

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PubMed1987

[Effect of 1,2-dimethylhydrazine on the level of specific binding and ligand affinity to the estradiol receptor in the cytosol of uterine tissue in CBA mice].

1,2-dimethylhydrazine (DMH) inducing uterine sarcomas in CBA mice was studied for its prolonged effect on the level of specific binding and affinity to the estradiol receptors in cytosol fraction of CBA mice uterine tissue. It is shown that the dissociation constant 3H-estradiol-17 beta with a receptor protein in the cytosol of uterine tissue of DMH treated mice was slightly higher than in control mice. The theoretical number of the ligand binding sites with receptor protein and the level of free binding sites of estrogen receptors were higher in DMH-treated animals than in control mice during the whole period of observation.

1,2-Dimethylhydrazine↗
PubMed1987

Three new rat colon tumour cell lines from 1,2-dimethylhydrazine induced adenocarcinomas: morphology, karyotype and clonogenicity.

Three different tumour cell lines (Per113, Per192, Per237) were established from colon adenocarcinomas induced by 1,2-dimethylhydrazine (DMH) inbred male Wistar/Wag rats. Each cell line had epithelial morphology and an abnormal karyotype. The three cell lines were clonogenic in semi-solid medium, but differed in growth factor response, culture characteristics and karyotype. Each cell line was stimulated differentially by epidermal growth factor (EGF) and bombesin in culture. Only Per192 would passage in vivo in athymic nude mice. Per 113 had modal chromosome number of 70 with multiple structural abnormalities; Per237 had 43 chromosomes with consistent trisomy of chromosome I; 20-25% of the cells in line Per192 were in the tetraploid range with multiple copies of chromosome I.

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PubMed1987

[Effect of the duration of administration of 1,2-dimethylhydrazine on its carcinogenic effect].

The (CBA x C57Bl)F1 female mice were treated with weekly injections of 1,2-dimethylhydrazine (DMH) at a dose rate of 4.15 mg/kg of body weight during different time periods. Relations between the incidence of organ specified particular tumours depend on the total DMH dose. Incidence of haemoblastoses decreases with an increase in the DMH dose. Dose relationships of the tumour incidence are analyzed statistically by the method with intercurrent mortality corrections and carcinogen effect expressed by relations of the observed and expected numbers.

1,2-Dimethylhydrazine↗
PubMed1986

[Serial endoscopic examinations of 1,2-dimethylhydrazine induced colon tumors in rat and effects of fecal stream].

Some new aspects regarding 1,2-dimethylhydrazine induced rat colon tumors were obtained from the findings of weekly endoscopic examinations of induced tumors and their histological results. It was observed endoscopically that each tumor had a different speed of growth. There was no relation between the time when a tumor appeared and the depth of its invasion at sacrifice. Biopsies were taken from several tumors at an early stage when these tumors were recognized endoscopically. The histological findings of the biopsy specimens were all compatible with adenocarcinoma. The total number of tumors increased with time. As a second step, the effect of fecal stream upon the carcinogenesis in rats of our experimental model was investigated by periodic endoscopy before and after fecal diversion, and by histological examination. Without a fecal stream microscopic foci of atypical glands did not grow to become visible tumors. However, a tumor which had already become visible in endoscopy grew in the absence of a fecal stream. It is possible to say that the carcinogenesis of this experimental model has two distinct phases, i.e., initiation and promotion. Our result could give valuable information for the study of carcinogenesis in human large bowel.

1,2-Dimethylhydrazine↗
PubMed1986

Activation of the colon carcinogen 1,2-dimethylhydrazine in a rat colon cell-mediated mutagenesis assay.

Suspensions of rat colon epithelial cells metabolized the potent colon carcinogen, 1,2-[14C]dimethylhydrazine (DMH), into 14C-labeled, alkali-soluble volatile products, presumably CO2. The colon cell suspensions, however, were less effective than rat hepatocyte suspensions. In addition, we used a cell-mediated mutagenesis assay to test rat colon epithelial cells grown from tissue explants for their ability to metabolize DMH into products mutagenic for human P3 teratoma cells. Mutagenesis in the P3 cells was indicated by an acquired resistance to 6-thioguanine. Cocultivation of the colon cells with the P3 cells in the cell-mediated assay resulted in mutagenesis, whereas in the absence of the colon cells, no mutagenesis by DMH was observed. Similar results were obtained in a hepatocyte-mediated mutagenesis assay. Colon cells were also able to activate another carcinogen, benzo(a)pyrene, into products mutagenic for the P3 cells. Individual epithelial clonal populations isolated from the colon cultures grown from tissue explants, however, expressed different capacities to activate DMH and benzo(a)pyrene into mutagens, and a high degree of DMH activation by cells from a colon clone was not necessarily associated with a similar degree of benzo(a)pyrene activation. Our results indicate that the colon itself contains epithelial cell types capable of effectively converting DMH into mutagenic (and presumably carcinogenic) products without necessarily involving intermediary metabolism by hepatocytes as previously thought.

1,2-Dimethylhydrazine↗
PubMed1986

[Effect of 1,2-dimethylhydrazine on the estrous cycle in different strains of mice].

CBA, C3HA, C57Bl, Balb/c and DBA female mice received 20 subcutaneous weekly injections of 1,2-dimethylhydrazine in the dose of 8 mg/kg body weight. Estrous cycles were studied in vaginal smears taken 5, 10, 15 and 20 weeks after the 1st DMH injection. In CBA strain susceptible to DMH induction of uterine sarcomas a persistent estrus was observed in 50% of mice after 5 to 10 DMH injections. In C3HA, C57B1, Balb/c and DBA strains resistant to the DNH induction of uterine sarcomas persistent estrus was not observed; the majority of these mice retained a normal estrus cycle. Persistent diestrus which was absent in susceptible CBA mice was found in these resistant strains. No CBA females with a normal estrous cycle were observed after the beginning of DMH treatment. The differences in the estrous cycle found in the mouse strains treated with DMH may partly explain the observed strain differences in the susceptibility to the DMH induction of uterine sarcomas.

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PubMed1985

Potentiation of 1,2-dimethylhydrazine-induced anal carcinoma by epidermal growth factor in mice.

Because epidermal growth factor (EGF) can modify cell proliferation in the gastrointestinal tract, effects of EGF were studied on the development of colonic, rectal, and anal neoplasms in male mice treated with 1,2-dimethylhydrazine (DMH) (20 mg/kg/wk for 20 weeks). DMH treatment caused a 13% increase in colonic RNA content, a 16% increase in DNA content, and 28% greater crypt depth. EGF (5 micrograms on alternate days during weeks 20 to 22) administered to DMH-treated mice produced no additional changes in colonic mucosa. At 30 weeks colorectal tumors were present in 13 of 20 mice treated with DMH (mean number of tumors per mouse 2.3 +/- 0.5) and 18 of 24 mice (mean 2.6 +/- 0.7) treated with DMH and EGF. Anal tumors were present in two of 20 DMH-treated mice (mean 0.1 +/- 0.07) but in eight of 24 DMH-EGF-treated mice (mean 0.33 +/- 0.1) (X2 = 4.84; p less than 0.05 for prevalence). Although EGF in this dose has no effect on the frequency of colorectal adenocarcinomas, the frequency of anal squamous cell carcinomas is increased more than three fold.

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