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PubMed1985

Induction of nephroblastoma-like renal tumours in rats by a single dose of 1,2-dimethylhydrazine.

A single injection of 1,2-dimethylhydrazine (200 mg/kg s.c.) resulted in the development of renal tumours in 70 per cent of treated rats within 1 year. The tumours were frequently bilateral (36 per cent) and grew to a large size (up to 100 g) before causing death. Lung metastases were found in one case. Histologically, the majority of the tumours (73 per cent) exhibited the classical triphasic morphological features of nephroblastoma (Wilms' tumour) with varying proportions of epithelial (glomeruloid and tubular structures), stromal (fibrous tissue, smooth muscle, cartilage) and blastematous elements. This pathological resemblance to human nephroblastoma suggests the possibility of using dimethylhydrazine-induced renal tumours as a model of Wilms' tumour.

1,2-Dimethylhydrazine↗
PubMed1988

Premalignant alterations in the glycosphingolipids of small intestinal mucosa of rats treated with 1,2-dimethylhydrazine.

1,2-Dimethylhydrazine is a procarcinogen with selectivity for the colon and proximal small intestine. In weekly subcutaneous (s.c.) doses of 20 mg/kg body weight, this agent produces colonic and proximal small intestinal tumors in a high percentage of rodents with a latency period of approximately six months. To determine whether alterations in the glycosphingolipid content of rat proximal and/or distal small intestinal mucosa existed before the development of dimethylhydrazine-induced cancer, rat were given s.c. injections of this agent (20 mg/kg body weight per wk) or diluent for five wk. Animals were killed at this time, and mucosa was isolated from each small intestinal segment of both groups. Glycosphingolipids then were extracted from these tissues and analyzed by high performance thin layer chromatography and gas liquid chromatography. The results of these studies demonstrated that (1) the content of neutral and acidic glycosphingolipids was significantly decreased (approximately 20%) in the proximal small intestine of treated rats compared with their control counterparts; (2) no significant difference in the glycosphingolipid content was seen, however, in the distal small intestinal mucosa of control and treated rats; and (3) while significant differences were noted in the majority of fatty acids of GM3, glucosyl- and globotriaosylceramide in the proximal small intestine of control and treated animals, differences in the fatty acids of these glycosphingolipids in the distal segment of these groups were confined to stearic (18:0) acid and/or arachidic (20:0) acid.

1,2-Dimethylhydrazine↗
PubMed1985

Spin-trapping of methyl radical in the oxidative metabolism of 1,2-dimethylhydrazine.

A carbon-centered free radical formed during oxidative metabolism of 1,2-dimethylhydrazine has been spin-trapped with alpha-(4-pyridyl-1-oxide)N-tert-butyl nitrone and 2-methyl-2-nitrosopropane. In the horseradish peroxidase/H2O2 catalyzed oxidation, the trapped species was identified as the methyl radical by the characteristic 1:3:3:1 quartet pattern of the 2-methyl-2-nitroso propane adduct. A carbon-centered radical is also formed during microsomal oxidation of 1,2-dimethylhydrazine in the presence of NADPH. However, the alpha-(4-pyridyl-1-oxide)N-tert-butyl nitrone trapped radical has not been unambiguously identified in this latter instance. These results may be of importance in regard to both carcinogenic and antitumor properties of 1,2-disubstituted hydrazine derivatives.

1,2-Dimethylhydrazine↗
PubMed1982

Chemical interactions with herpes simplex type 2 virus: enhancement of transformation by hydrazine and 1,2-dimethylhydrazine.

Quantitative assays for the morphological transformation of 3T3 Swiss mouse cells by herpes simplex type 2 virus (HSV-2) were employed to examine the effect on cell transformation of chemical carcinogens and suspected carcinogens. Exposure of the cells to the chemical compound, followed by virus infection, resulted in enhancement of transformation when compared to that observed with chemical or virus alone. Enhancement occurred in tests utilizing either UV light-inactivated HSV-2 (strain 333) or a temperature-sensitive (ts) mutant of HSV-2 (A8(293)]. A series of seven ts-mutants were tested and exhibited varying degrees of transformation. Enhancement of transformation occurred in cells treated with hydrazine (HZ) and 1,2-dimethylhydrazine (SDMH). No enhancement occurred when cells were treated with monomethylhydrazine, 1,1-dimethylhydrazine and the jet fuels JP-5, JP-10, RJ-4 and RJ-5. A strong time dependence after treatment was demonstrated with some enhancement seen at 6 h after chemical treatment but the greatest enhancement appeared when virus infection began after 24 h of chemical exposure.

1,2-Dimethylhydrazine↗
PubMed1983

Comparison of the effects of 1,2-dimethylhydrazine and cyclophosphamide on micronucleus incidence in bone marrow and colon.

An in vivo micronucleus assay has been developed that utilizes colonic epithelial cells. The genotoxic effects of 1,2-dimethylhydrazine (54-07-3), a colon carcinogen, and of the nitrogen mustard, cyclophosphamide (50-18-0), on the bone-marrow polychromatic erythrocytes and on colonic epithelium from mice were compared using micronucleus induction in each organ as the end point. In the bone marrow, cyclophosphamide was a potent inducer of micronuclei, while 1,2-dimethylhydrazine administration had little effect on the micronucleus incidence. In the colon, 1,2-diemthylhydrazine was an effective inducer of micronuclei. Thus, the colonic micronucleus assay appears to be a potentially useful test for the detection of colon carcinogens.

1,2-Dimethylhydrazine↗
PubMed1996

Dose-response relationship for rat liver DNA damage caused by 1,2-dimethylhydrazine.

An experimental approach was taken to the question of dose-response curves for chemical carcinogenesis, using DNA damage as a biomarker. Female rats were give 13 different doses of 1,2-dimethylhydrazine (from 1.4 to 135,000 micrograms/kg) and the subsequent hepatic DNA damage was determined by the alkaline elution technique. DMH doses below 450 micrograms/kg did not significantly damage DNA; all DMH doses of 1000 micrograms/kg or higher damaged rat hepatic DNA (P < 0.05). In this study the x values (dose) ranged over five orders of magnitude and the y values (DNA damage) ranged 30-fold. Ten different regression models (linear, quadratic, cubic, power, and six nonlinear transition models) were compared in their ability to fit the experimental data. With respect to log transformed dose, the six nonlinear transition equations fit the data considerably better than the four power type of equations. A sigmoid model fit to the log transformed dose of 1,2-dimethylhydrazine had an r2 of 0.9979, a degree of freedom adjusted r2 of 0.9969, a F-statistic of 1,457, and a fit standard error of 0.50. With respect to untransformed dose, only three equations (sigmoid, cascade and gaussian cumulative) could creditably fit the DMH data. The experimental results are interpreted with respect to hormesis, use of log transformed dose, sigmoid dose-response models, thresholds of biological response and cancer risk assessment.

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PubMed1998

Organ-specific genotoxicity of the potent rodent colon carcinogen 1,2-dimethylhydrazine and three hydrazine derivatives: difference between intraperitoneal and oral administration.

We used a modification of the alkaline single cell gel electrophoresis (SCG) (Comet) assay to test the in vivo genotoxicity of four hydrazine derivatives--1,2-dimethylhydrazine (SDMH), 1,1-dimethylhydrazine (UDMH), hydrazine (HZ), and procarbazine (PCZ)--in mouse liver, lung, kidney, brain, and bone marrow, and in the mucosa of stomach, colon, and bladder. Mice were sacrificed 3 and 24 h after intra-peritoneal (i.p.) and oral (p.o.) administration. SDMH at 20 mg/kg i.p. yielded statistically significant DNA damage in all tested organs except for lung. In the gastrointestinal tract, SDMH was genotoxic in the stomach and the colon after i.p. treatment but only in the colon after 20 and 30 mg/kg p.o. treatment. UDMH at 50 mg/kg i.p. yielded DNA damage in the liver and lung at 3 h. PCZ at 200 mg/kg i.p. caused DNA damage in the liver, kidney, lung, brain, and bone marrow. UDMH and PCZ were positive in the stomach and colon p.o. but not by i.p. treatment. HZ at 100 mg/kg yielded DNA damage in the stomach, liver, and lung when given i.p. and in the brain when p.o. Thus, the administration route is important when evaluating organ-specific genotoxicity in multiple organs.

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PubMed1984

Effects of cimetidine and indomethacin on the growth of dimethylhydrazine-induced or transplanted intestinal cancers in the rat.

The effects of cimetidine and indomethacin on the growth of dimethylhydrazine induced or transplanted intestinal tumours in the rat have been studied. Cimetidine is a histamine type 2 receptor antagonist and indomethacin is an inhibitor of prostaglandin synthesis. Two models of rat intestinal tumours were used: a colon carcinoma line transplantable in syngeneic animals and intestinal tumours induced by dimethylhydrazine treatment of Sprague-Dawley rats. Cimetidine and indomethacin were given in drinking water, alone or in combination. Cimetidine had no effect on the growth of transplanted colon cancer but significantly increased the incidence of chemically-induced tumours, with a tendency toward more invasive and metastatic tumours than in the control animals. Indomethacin did not significantly modify the incidence or other characteristics of the tumours in any of the models. This result is at variance with a protective effect of indomethacin on chemically-induced rat colon cancer previously reported by others.

1,2-Dimethylhydrazine↗
PubMed1993

Effect of dietary vitamin D3 (cholecalciferol) on colon carcinogenesis induced by 1,2-dimethylhydrazine in male Fischer 344 rats.

This study examined the effect of increasing dietary vitamin D on chemically induced colon carcinogenesis. Male Fischer 344 rats were first injected with 1,2-dimethylhydrazine (200 mg/kg) and then fed one of five dietary levels of vitamin D as cholecalciferol (250, 1,000, 2,000, 4,000, and 10,000 IU/kg diet) for nine months. Dietary vitamin D3 had no effect on weight gain. Plasma 25-hydroxyvitamin D3 levels were similar for the 1,000 and 2,000 IU/kg groups but varied in a dose-related manner for the other groups. Vitamin D did not significantly alter the tumor incidence in either the distal or the proximal colon. No significant differences in the labeling index were found in either the proximal or the distal colon. Within the distal colon, the proliferative zone increased in a dose-related manner. Distribution of labeled cells within the crypt compartments was not affected by dietary vitamin D. Bone and serum minerals in general were unaffected by dietary vitamin D. This study shows that, at this level of dietary calcium, vitamin D did not affect 1,2-dimethylhydrazine-induced colon carcinogenesis.

1,2-Dimethylhydrazine↗
PubMed1996

Endogenous antioxidant status in neoplastic and adjacent tissues in 1,2-dimethylhydrazine-induced colon cancer in rats: effects of olsalazine.

There is much evidence suggesting a possible role of reactive oxygen-derived substances in the pathogenesis of both ulcerative colitis and colon cancer. The antioxidant effects of 5-aminosalicylic acid (the active moiety of olsalazine) on induction of colon cancer in an experimental model using 1,2-dimethylhydrazine were studied in male Wistar rats. The levels of reduced glutathione were significantly (P < 0.01) decreased (by approximately 50%) in neoplastic tissues of rats receiving 1,2-dimethylhydrazine alone and olsalazine treatment significantly (P < 0.01) reduced the extent of this alteration. Adjacent tissues from rats receiving either carcinogen alone or carcinogen and olsalazine showed comparable levels of glutathione and these were significantly (P < 0.01) lower than corresponding control values and higher than corresponding values from neoplastic tissues. Activity of the glutathione regenerating enzyme glutathione reductase was significantly (P < 0.01) decreased (by approximately 40%) in neoplastic colonic tissue and this alteration was unaffected by olsalazine treatment. Neither carcinogen nor olsalazine treatment caused alterations in activity of glutathione reductase in adjacent tissue as compared with corresponding control values. Activity of the glutathione utilizing enzyme glutathione peroxidase was significantly (P < 0.01) increased (almost doubled) in neoplastic tissue of rats treated with carcinogen alone. Olsalazine treatment significantly (P < 0.01) reduced the elevation in glutathione peroxidase activity in neoplastic tissues of rats treated with the carcinogen. Glutathione peroxidase showed comparable activity in adjacent tissue from rats treated with either carcinogen alone or a combination of carcinogen and olsalazine and these values were significantly (P < 0.01) lower than corresponding control values. Colonic neoplastic tissues from all experimental groups of animals showed a small, but statistically significant (P < 0.05), decrease in superoxide dismutase activity compared with that in corresponding tissues from control animals.

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PubMed1992

Identification of C8-methylguanine in the hydrolysates of DNA from rats administered 1,2-dimethylhydrazine. Evidence for in vivo DNA alkylation by methyl radicals.

C8-Methylguanine was identified in the neutral hydrolysates of DNA isolated from the liver or colon tissue of rats administered 1,2-dimethylhydrazine. In all the samples examined, the biologically isolated adducts were characterized by co-elution with synthetic C8-methylguanine under different high pressure liquid chromatography conditions. The sample isolated from liver DNA was also identified by UV spectroscopy at different pH values and by mass spectrometry. The estimated yields of C8-methylguanine obtained in hydrolysates of DNA from the liver or colon tissue were comparable to those of O6-methylguanine. C8-Methylguanine was not detected when the spin trap alpha-(4-pyridyl-1-oxide)-N-tert- butylnitrone was administered together with 1,2-dimethylhydrazine. The spin trap also inhibited N7-methylguanine and O6-methylguanine yields, although to a lesser extent. These results constitute the first evidence that DNA alkylation by carbon-centered radicals can occur in vivo.

1,2-Dimethylhydrazine↗
PubMed1991

[Changes in the adhesion between enterocytes in short-term exposures to antioxidants and 1,2-dimethylhydrazine].

Ascorbic acid, alpha-tocopherol acetate, butilated hydroxytoluene, butilated hydroxyphenol, and sodium selenite have no influence on the intercellular adhesion in colon epithelium of mice. These antioxidants can drop or prevent from the increase in colonocyte adhesion induced by a single injection of colon carcinogen--1,2-dimethylhydrazine. With a simultaneous instillation of antioxidants and the colon carcinogen, the protective effect drops to zero in the following line: ascorbic acid--alpha-tocopherol acetate--butilated hydroxytoluene--sodium selenite--butilated hydroxyphenol. On instillation of the antioxidants 8-9 days after single injections of 1,2-dimethylhydrazine, the protective effect dropped to zero in the line: ascorbic acid--sodium selenite--alpha-tocopherol acetate--butilated hydroxytoluene. The data obtained give rise to a conclusion that the investigated effects of antioxidants may correlate with their anticarcinogenic actions.

1,2-Dimethylhydrazine↗
PubMed1989

1,2-Dimethylhydrazine-induced alterations in N1-acetylspermidine levels and spermidine N1-acetyltransferase activity in rat colonic mucosa.

To determine whether alterations in the "reverse" or "conversion" pathway for putrescine formation were involved in the induction of colonic tumors by 1,2-dimethylhydrazine, male albino rats of the Sherman strain were given injections s.c. of this agent (20 mg/kg body weight/week) or diluent for 5, 10, 15, and/or 26 weeks. Animals were sacrificed at each of these time periods and polyamine levels, including N1- and N8-acetylspermidine, as well as the activities of ornithine decarboxylase, spermidine N1-acetyltransferase and polyamine oxidase were measured and compared in rat proximal and distal colonic mucosa of each group. The results of these studies demonstrated that: (a) N1- and N8-acetylspermidine levels were similar in the control and treated proximal colonic segments at all time periods examined; (b) N1- and N8-acetylspermidine levels were also similar in the control and treated distal colonic segments at 5 and 10 weeks; (c) at 15 weeks the level of N1-acetylspermidine, but not N8-acetylspermidine, however, was increased in the treated distal colonic segment secondary to increases in the activity of spermidine N1-acetyltransferase; and (d) at 26 weeks, the level of N1-acetylspermidine remained higher in treated distal "uninvolved" colonic tissue and were markedly elevated in colonic tumors in both segments. Based on these findings, it would appear that the reverse pathway for putrescine formation may be involved in the 1,2-dimethylhydrazine-induced malignant transformation process of the rat colon.

1,2-Dimethylhydrazine↗
PubMed1984

Stimulation of rat colonic crypt cell proliferative activity by wheat bran consumption during the stage of 1,2-dimethylhydrazine administration.

The effect on colonic epithelial cytokinetics of feeding a 20% wheat bran dietary supplement, either during and/or after the stage of carcinogen administration with 1,2-dimethylhydrazine, was examined in 48 male Sprague-Dawley rats fed defined diets for up to 31 weeks. Nutrient intake and body weight gain were equivalent in all groups of animals. All subgroups of rats fed bran, either during and/or after carcinogen administration, developed colonic crypt cell hyperplasia (p less than 0.05), this being greater in the proximal than in the distal colon. Autoradiographic studies showed a significant increase in proximal colonic crypt cell-labeling index, proliferation zone size, and migration distance in those rats fed wheat bran during the period of carcinogen administration (p less than 0.05). The increase in epithelial cell proliferation activity was most marked in the upper two-thirds of the crypt. These data show that there is a greater stimulation of crypt cell proliferation activity when wheat bran is consumed during the stage of carcinogen administration as compared to the stage following carcinogen exposure. This alteration in mucosal cytokinetics appears to be the mechanism by which wheat bran consumption enhances rat colon carcinogenesis during the period of dimethylhydrazine treatment.

1,2-Dimethylhydrazine↗
PubMed1984

An investigation into the mechanism of co-carcinogenesis of dietary cholesterol during the induction of colon cancer in rats by 1,2 dimethylhydrazine.

The mechanism by which dietary cholesterol facilities colon carcinogenesis was investigated in the dimethylhydrazine-induced rat colon cancer model. Fifty female Wistar rats received a standard course of dimethylhydrazine (DMH) injections (40 mg/kg/week subcutaneously for ten weeks) while being fed Vivonex, a cholesterol-free elemental diet. Animals were allocated to one of five dietary regimens. One control group received Vivonex with added cholesterol (10 mg/100 ml Vivonex/rat/day) throughout the experiment, while another group received Vivonex alone. The remaining three groups received added cholesterol exclusively before, during or after the ten week DMH induction period. The experiment continued for over 500 days, and was evaluated by comparing, between groups, the time taken for the development of objective signs of colonic disease (time to tumour presentation or TTP). Animals either died spontaneously or were killed and autopsied. Colon cancers were confirmed histologically in every animal. The results showed that cholesterol feeding throughout the experiment or during the DMH induction period reduced the TTP compared to controls (p less than 0.05). Cholesterol prefeeding had no such effect. In the after group, the TTP was correspondingly delayed (p less than 0.05). Cholesterol-fed controls and groups receiving cholesterol during or after the DMH induction had more colon tumours and/or a greater incidence of metastases than cholesterol-free controls or those pre-fed cholesterol. The findings indicate a direct relationship between timing of cholesterol exposure and signs of colon cancer, and demonstrate that dietary cholesterol has promoter-like characteristics.

1,2-Dimethylhydrazine↗
PubMed1984

Effects of 1,2-dimethylhydrazine on the number of epithelial cells present in the villi, crypts, and mitotic pool along the rat small intestine.

Young adult male rats received 1,2-dimethylhydrazine (25 mg/kg) twice weekly for 2 months and once a week thereafter for up to 6 months. Histological samples of duodenum, jejunum, and upper, mid-, and terminal ileum were prepared from groups killed at each month. Using cell counts, the average number of epithelial cells was determined per representative section of villi and crypts and was used as an index of villus size and crypt size, respectively. The average number of mitotic figures in representative crypt sections was also determined. All three parameters increased during treatment, and the increments showed a specific pattern in relation to time and intestinal region. Mitotic number showed a consistent change all along the small intestine: close to 20% rise by 3 months; decrease to near control level by the fourth month; and a rise thereafter. Probably, a systemic stimulation of mitotic activity by 1,2-dimethylhydrazine took place. The crypt size index changed similarly, showing highly significant correlation with mitotic number. This correlation indicated that average mitotic time and cell cycle time remained unchanged and the number of divisions increased in progenitor cells. Calculations showed that only a fraction of the progenitor cells was involved. These were probably "initiated" cells. There was a net increase of initiated cell numbers with time, but a sharp drop at 4 months indicated that there is a mechanism inducing a regression of the initiated cell population. Villus size increased linearly in the duodenum and jejunum. In the ileum, there was also a net increase but with some initial fluctuation. In general, villus size seemed to increase so as to maintain a fairly stable turnover time. This would mean that the increased mitotic activity was balanced by increasing differentiation.

1,2-Dimethylhydrazine↗
PubMed1984

Morphology and distribution of 1,2-dimethylhydrazine dihydrochloride-induced colon tumors and their relationship to gut-associated lymphoid tissue in the rat.

The histopathology and relationship of sym-dimethylhydrazine dihydrochloride [(DMH) CAS: 306-37-6; 1,2-dimethylhydrazine dihydrochloride]-induced colon tumors to colonic lymphoid aggregates were examined in outbred male Sprague-Dawley rats treated with saline or DMH and sacrificed at three intervals after treatment. The ratio of polypoid:sessile tumors was 71:29 four months after DMH treatment and 62:38 when tumors were fully developed. Colonic lymphoid aggregates were found 3-5 cm from the cecal-colonic junction, near the flexure of the ascending and transverse colon, and 3-5 cm from the rectum. There were no significant differences between saline-treated and DMH-treated rats regarding the size, cellularity, and number of lymphoid aggregates per rat. A significant association (P less than .001) was seen between tumor development and the presence of a lymphoid aggregate in a given segment of the colon. Sessile adenocarcinomas, but not polypoid tumors, were significantly associated (P less than .001) with lymphoid aggregates and usually presented as mucinous tumors adjacent to or intermixed with the lymphoid tissue.

1,2-Dimethylhydrazine↗
PubMed1983

Effect of alterations in the quality and quantity of dietary fat on 1,2-dimethylhydrazine-induced colon tumorigenesis in rats.

The effect of alterations in the quality and quantity of dietary fat on 1,2-dimethylhydrazine-induced colon cancer in rats was studied. Weanling Sprague-Dawley rats were fed semipurified diets containing 24% beef fat, 24% corn oil, 24% Crisco, or the three fats in equal parts to make a total of 5% fat with other macronutrients and micronutrients adjusted to balance the ratios of nutrient to calorie. After 4 weeks of dietary treatment, all rats, except vehicle-treated animals, received 1,2-dimethylhydrazine (15 mg/kg) by gavage, once a week for 5 weeks. The animals were fed the experimental diets until intestinal tumors developed, and surviving animals were sacrificed at 60 weeks. There was no effect of any of the high-fat diets tested on intestinal tumor incidence, latency, size, or frequency. All groups contained the same proportion of adenomas (less than 3%) as well as adenocarcinomas classified as mucinous. In the group fed 24% Crisco, tumors occurred with greater frequency in the proximal section of the colon than in lower segments, but the distribution was approximately uniform in the other groups. Cumulative probability of death with colon carcinoma was lowest in the 24% Crisco group, but the other high-fat groups did not differ significantly from the 5% mixed fat group nor from one another.

1,2-Dimethylhydrazine↗