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PubMed1995

Effects of dietary fibre on dimethylhydrazine-induced changes in prostanoid concentrations in rat colonic mucosa.

1. This study was designed to elucidate the effects of guar gum, a dietary fibre, on changes in prostanoid contents induced by 1,2-dimethylhydrazine, a carcinogenic agent, in rat colonic mucosa. 2. Prostanoid contents were determined using high performance liquid chromatography; five prostanoids, namely 6-keto-prostaglandin F1 alpha, prostaglandin F2 alpha, prostaglandin E2, prostaglandin D2 and thromboxane B2, were detected. 3. Four subcutaneous injections of dimethylhydrazine, 60 mg/kg every 6 days, increased the mucosal concentrations of prostaglandin E2 and thromboxane B2 by approximately 50%. Other prostanoids did not change significantly throughout the experiments. 4. In rats treated with dimethylhydrazine and a fibre diet a significant increase in thromboxane B2 content was not observed, although a significant increase in prostaglandin E2 content was observed. These effects were observed in rats fed with fibre diet over 20 days but not observed in rats fed with fibre diet over 10 days. 5. From these results and the report that aspirin use at low doses is effective in the reduction of the risk of fatal colonic cancer, inhibiting thromboxane B2 synthesis by fibre diet might be involved in the protective effect against the occurrence of colonic cancer.

1,2-Dimethylhydrazine↗
PubMed1982

Dietary cholesterol deprivation improves survival and reduces incidence of metastatic colon cancer in dimethylhydrazine-pretreated rats.

Cholesterol feeding of rats with colon cancer induced by dimethylhydrazine results in reduced survival and an increased incidence of metastatic colon cancer. As cholesterol may be implicated in the induction or maintenance of the metastatic process, an experiment was designed to determine whether rats with colon cancer would benefit from the removal of cholesterol from the diet. Female Wistar rats were treated with a colon cancer-inducing regimen of dimethylhydrazine (40 mg/kg/week for 10 weeks) while being fed on a standard cholesterol-containing rat pellet diet. After two rats had died spontaneously of histologically proven adenocarcinoma of the colon at 24 weeks, the remaining rats were randomly allocated in groups of 15 to one of three dietary regimens. Group S continued to receive standard pellet diet, group V were fed on Vivonex alone and group VC were fed Vivonex plus cholesterol (10 mg/100 ml Vivonex). Each group was assessed for survival and incidence of histologically proven metastatic disease. There were no differences in either survival or incidence of metastases when groups S and VC were compared. In the cholesterol deprived group V, however, there was a significant increase in survival compared with groups S and VC (p less than 0.02) and this was due to a significant reduction in the incidence of metastases (p less than 0.05). Cholesterol deprivation therefore benefits rats with established colon cancer induced by dimethylhydrazine by improving survival and reducing the incidence of metastases.

1,2-Dimethylhydrazine↗
PubMed1991

K-ras mutations in 1,2-dimethylhydrazine-induced colonic tumors: effects of supplemental dietary calcium and vitamin D deficiency.

Recent studies from our laboratory have demonstrated that dietary supplemental calcium had no significant effect on the incidence of 1,2-dimethylhydrazine-induced colonic tumors, but did decrease the number of rats with multiple tumors and reduced tumor size. Moreover, concomitant vitamin D deficiency appeared to abolish these protective effects of calcium on colonic tumors in this experimental model. To date, however, the mechanism(s) involved in these phenomena remain unclear. In order to address these important issues, 1,2-dimethylhydrazine-induced colonic tumors from animals on control, Ca(2+)-supplemented, vitamin D-sufficient, and Ca(2+)-supplemented, vitamin D-deficient diets were examined for the presence of ras oncogene mutations. DNA was extracted from each of these tumors. Targeted areas of K-ras and H-ras genes were amplified by the polymerase chain reaction and analyzed for point mutations using allele-specific oligonucleotide hybridization and subsequent DNA sequencing. The results of these studies demonstrated that: (a) approximately one-third of 1,2-dimethylhydrazine-induced colonic carcinomas in the control group had K-ras G to A mutations; (b) no mutations, however, were detected in the cancers of the calcium-supplemented group; (c) concomitant vitamin D deficiency abolished the antimutagenic effect of dietary calcium supplementation (e.g., approximately one-third of cancers in this group again had detectable K-ras mutations); and (d) no H-ras point mutations were detected in colonic tumors from any group. These findings suggest that alterations in K-ras mutations may be one possible mechanism by which calcium and vitamin D status influence colonic carcinogenesis in this experimental model.

1,2-Dimethylhydrazine↗
PubMed1990

Mutagenesis of mouse intestine in vivo using the Dlb-1 specific locus test: studies with 1,2-dimethylhydrazine, dimethylnitrosamine, and the dietary mutagen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline.

The ability of three model carcinogens, 1,2-dimethylhydrazine, dimethylnitrosamine, and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, to induce mutation in a novel in vivo assay in mouse intestine has been examined. The assay is based on mutations at the Dlb-1 locus which determines the tissue specific pattern of expressio of the binding site for the lectin Dolichos biflorus agglutinin. In C57BL/6J x SWR F1 mice Dlb-1 mutants are recognized as clones of epithelial cells not staining with a peroxidase conjugate of D. biflorus agglutinin. Chronic administration of 1,2-dimethylhydrazine (20 mg/kg/week s.c. for 10 weeks) induced Dlb-1 mutants, whereas administration of a single dose did not. Similarly, chronic dimethylnitrosamine treatment p.o. (0.001% in drinking water for 8 weeks) induced Dlb-1 mutants, but acute administration did not. In contrast, neither chronic nor acute treatment of the mice with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline induced Dlb-1 mutations. The activities of 1,2-dimethylhydrazine, dimethylnitrosamine, and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in the Dlb-1 assay more accurately reflect their carcinogenic potential than do many in vitro bioassays.

1,2-Dimethylhydrazine↗
PubMed1988

Dietary whey protein inhibits the development of dimethylhydrazine induced malignancy.

This study investigates the influence of two formula diets containing 20 g/100 g diet of either whey protein concentrate or casein or Purina mouse chow, on the humoral immune responsiveness and dimethylhydrazine induced colon carcinogenesis in A/J mice. After 20 weeks of dimethylhydrazine treatment, the number of plaque forming cells per spleen, following intravenous inoculation with 5 X 10(6) sheep red blood cells, was nearly three times greater in the whey protein-fed group than in the casein-fed mice although both values were substantially below normal. After 24 weeks of dimethylhydrazine treatment the incidence of tumors in the whey protein-fed mice was substantially lower than that in mice fed either the casein or Purina diet. Similarly, the tumor area was less in the whey protein group in comparison to either the casein or Purina groups, with some difference between casein and Purina groups. Body weight curves were similar in all dietary groups. In conclusion, a whey protein diet appears to significantly inhibit the incidence and growth of chemically induced colon tumors in mice.

1,2-Dimethylhydrazine↗
PubMed1987

Enzymatic activation of the carcinogens 2-phenylethylhydrazine and 1,2-dimethylhydrazine to carbon-centered radicals.

Spin-trapping experiments demonstrate that oxidation of 1,2-dimethylhydrazine and 2-phenylethylhydrazine generates a comparable yield of carbon-centered radicals when catalyzed by horseradish peroxidase - H2O2. Using oxyhemoglobin as the catalyst, 2-phenylethylhydrazine oxidation generates ten times more carbon-centered radicals than 1,2-dimethylhydrazine oxidation. This result is in agreement with oxygen consumption studies from which the apparent KM values of 8.0 mM and 72 mM were calculated for the oxyhemoglobin-catalyzed oxidation of 2-phenylethylhydrazine and 1,2-dimethylhydrazine, respectively. These differences in metabolic activation of mono- and disubstituted hydrazines may be of importance regarding the carcinogenic properties of these derivatives.

1,2-Dimethylhydrazine↗
PubMed1987

Premalignant alterations in the glycosphingolipid composition of colonic epithelial cells of rats treated with 1,2-dimethylhydrazine.

1,2-Dimethylhydrazine is a procarcinogen with selectivity for the colon. In weekly s.c. doses of 20 mg/kg of body weight, this agent produces colonic tumors in virtually 100% of rodents, with a latency period of approximately 6 months. To determine whether alterations in the glycosphingolipid content and composition of rat colonic epithelial cells existed before the development of dimethylhydrazine-induced colon cancer, rats were given s.c. injections of this agent (20 mg/kg body weight per week) or diluent for 5 weeks. Animals were sacrificed at this time period and colonocytes isolated from each group. Glycosphingolipids were then extracted from these cells and analyzed by thin-layer chromatography, high-performance liquid chromatography and gas-liquid chromatography. The results of these studies demonstrate that: (a) the content and relative percentages of globotriaosylceramide is increased, whereas hematoside and globotetraosylceramide are decreased in dimethylhydrazine-treated colonocytes compared to their control counterparts; and (b) differences in the enzymatic activities responsible for the biosynthesis of these glycosphingolipids appear to explain, at least partially, these compositional differences. The present data, therefore, suggest that alterations in certain glycosphingolipids may be an early event in colonic malignant transformation and, furthermore, that these alterations may prove useful in the detection of early colon cancer.

1,2-Dimethylhydrazine↗
PubMed1983

Morphometric study of the rat duodenal epithelium during the initial six months of 1,2-dimethylhydrazine carcinogenesis.

Male Wistar rats weighing 100 g received 1,2-dimethylhydrazine (25 mg/kg) s.c.) twice a week for 2 months and once a week thereafter for an additional 4 months. Groups of four to six rats were sacrificed monthly. Paraffin sections of duodenum were prepared and stained with periodic acid-Schiff and hematoxylin for cell counts and with toluidine blue for measuring nucleolar area. As an index of villus size and crypt size, the mean number of epithelial cells per representative sections of villi and crypts were used. Mitotic activity was assessed by counting the mean number of mitotic figures per representative crypt section. Nucleolar area was assessed from the analysis of drawn (camera lucida) images of nucleoli of columnar cells at six levels of the epithelium: lower, mid, and upper parts of the crypts and villi. Villus size increased progressively during the 6-month treatment, from 272 +/- 2 (S.E.) to 349 +/- 8. Crypt size increased from 118 +/- 2 in a wavy fashion, showing maximum (139 +/- 5, 143 +/- 2) at 3 and 6 months and minimum (123 +/- 3, 127 +/- 1) at 1 and 4 months. Mitotic number displayed a similar pattern of increase so that the percentage of mitotic figures in the crypts (mitotic index) remained constant (about 5%) in control and experimental animals. Nucleolar area in the controls decreased with age from 4.2 +/- 0.08 sq micron in lower crypt at 1 month to 2.8 +/- 0.04 sq micron at 6 months. During 1,2-dimethylhydrazine treatment, lower crypt nucleoli increased to 4.5 +/- 0.12 sq micron after 3 months and decreased slightly thereafter, reaching 4.0 +/- 0.14 sq micron by the sixth month. The nucleoli furthermore decreased gradually along epithelium (nucleolar compaction) by an average of 0.23% per cell position in control as well as treated animals. It appeared, then, that the main effect of 1,2-dimethylhydrazine was the enlarging of the four parameters measured. This effect seemed to relate in some manner to tumor formation as all the enlargements were attenuated in intestinal tissue adjacent to tumors.

1,2-Dimethylhydrazine↗
PubMed1981

Effects of 1,2-symmetrical dimethylhydrazine on jejunocolic transposition in Sprague-Dawley rats.

In this experiment, a segment of the left colon including the upper part of the rectum was transposed to the upper jejunum, and a segment of upper jejunum was transposed to the left colon of the same animal. In another group, the same colon and jejunum segments were transsected and reanastomosed in place. A third group served as a normal control. After a recovery period, weekly s.c. 1,2-symmetrical dimethylhydrazine injections were begun. Each animal received a total of 20 injections at a dose of 20 mg/kg. Five weeks after the last 1,2-symmetrical dimethylhydrazine injection, 15 of 19 (79%) of the animals had one or more tumor(s) in the transposed colon segment, while none had tumor in the transposed jejunal segment. Transsected and reanastomosed animals showed the same distribution of tumors as did the normal control animals. All three groups had tumors at other sites in the colon and rectum. In addition, about 20% had tumors of the duodenojejunal area. These data indicate that the colonic mucosa is the primary target for the carcinogenic effect of 1,2-symmetrical dimethylhydrazine, independent of other variables such as the fecal stream.

1,2-Dimethylhydrazine↗
PubMed1994

Distribution of intestine-associated lymphoid tissue, aberrant crypt foci, and tumors in the large bowel of 1,2-dimethylhydrazine-treated mice.

Six-week-old male CF-1 mice were fed the AIN-76 diet, given eight weekly s.c. injections of either the colon carcinogen 1,2-dimethylhydrazine or saline, and killed 24 weeks after the last injection. Parameters measured in the large bowel included the incidence and locations of all intestine (gut)-associated lymphoid tissue (GALT) sites; the locations, incidence, and sizes of all aberrant crypt foci (ACF); and the incidence, locations, and types of all overt tumors. In saline-treated mice the distribution of GALT along the length of the large bowel was bimodal, with a majority peak of lymphoid nodules occurring in the distal large bowel and a minority peak occurring in the proximal large bowel. No ACF or tumors were present in the large bowel of the saline-treated mice. In 1,2-dimethylhydrazine-treated mice the majority of ACF were present in the middle third of the colon, between the two peaks of GALT, but the majority of the tumors were found over the GALT in the distal colon. There was a significant positive linear regression relationship between the numerical distribution of GALT and the numerical distribution of tumors along the length of the large bowel. There was no significant relationship between the distribution of ACF and the distribution of (a) tumors or (b) GALT along the length of the large bowel. Thus the numerical density of lymphoid nodules, not the numbers or distribution of ACF, was the significant predictor of the distribution of tumors in the large bowel of 1,2-dimethylhydrazine-treated mice. It is proposed that lymphoid nodules in the distal large bowel play a promotional role following initiation of colon carcinogenesis and that ACF have little if any malignant potential in the mouse.

1,2-Dimethylhydrazine↗
PubMed1977

Tumorigenic agents in unburned processed tobacco: N-nitrosodiethanolamine and 1,1-dimethylhydrazine.

Two tumorigenic agents, N-nitrosodiethanolamine and 1,1-dimethylhydrazine, have been isolated from tobacco for the first time. The former, a reportedly weak hepatic carcinogen in rats, varied in amounts from a low of 0.1 ppb in flue-cured tobacco not treated with the herbicide MH-30, to a high of 173 ppb in Burley tobacco to which the herbicide had been applied prior to harvesting. MH-30 (maleic hydrazide) used by farmers to remove 'suckers' from tobacco plants, is commonly formulated as the diethanolamine salt. 1,1-Dimethylhydrazine, reported to induce tumors in mice, ranged in amounts from 60 to 147 ppb, except in the case of Burley tobacco where none was detected (detection limit: 0.1 ng). The source of the nitrosamine in the tobacco appears to be the MH-30, whereas that of dimethylhydrazine has not been determined.

Diethylnitrosamine↗
PubMed2004

A novel mouse model for colitis-associated colon carcinogenesis induced by 1,2-dimethylhydrazine and dextran sulfate sodium.

AIM: To develop an efficient animal colitis-associated carcinogenesis model and to detect the expression of beta-catenin and p53 in this new model. METHODS: Dysplasia and cancer were investigated in mice pretreated with a single intraperitoneal injection of 20 mg/kg body mass of 1,2-dimethylhydrazine prior to three repetitive oral administrations of 30 g/L dextran sulfate sodium to give conditions similar to the clinically observed active and remission phases. Immunohistochemical staining of beta-catenin and p53 was performed on paraffin-imbedded specimens of animals with cancer and/or dysplasia, those without dysplasia and the normal control animals. RESULTS: At wk 11, four early-invasive adenocarcinomas and 36 dysplasia were found in 10 (90.9%) of the 11 mice that underwent 1,2-dimethylhydrazine-pretreatment with 3 cycles of 30 g/L dextran sulfate sodium-exposure. Dysplasia and/or cancer occurred as flat lesions or as dysplasia-associated lesion or mass (DALM) as observed in humans. Colorectal carcinogenesis occurred primarily on the distal portion of the large intestine. No dysplasia and/or cancer lesion was observed in the control groups with 1,2-dimethylhydrazine pretreatment or 3 cycles of 30 g/L dextran sulfate sodium exposure alone. Immunohistochemical investigation revealed that beta-catenin was translocated from cell membrane to cytoplasm and/or nucleus in 100% of cases with dysplasia and neoplasm, while normal membrane staining was observed in cases without dysplasia and the normal control animals. Nuclear expression of p53 was not detected in specimens. CONCLUSION: A single dose of procarcinogen followed by induction of chronic ulcerative colitis results in a high incidence of colorectal dysplasia and cancer. Abnormal expression of beta-catenin occurs frequently in dysplasia and cancer. This novel mouse model may provide an excellent vehicle for studying colitis-related colon carcinogenesis.

1,2-Dimethylhydrazine↗
PubMed1976

Colon carcinogenesis in germ-free rats with intrarectal 1,2-dimethylhydrazine and subcutaneous azoxymethane.

The effect of intestinal microflora on colon carcinogenesis by 1,2-dimethylhydrazine and azoxymethane was studied, with the use of germ-free and conventional female Fischer rats. At 7 weeks of age, germ-free and conventional rats were treated with 20 weekly intrarectal 1,2-dimethylhydrazine (20 mg per kg body weight per week) or subcutaneous azoxymethane (10 mg per kg body weight per week) doses and were autopsied 15 weeks later. Tumors were induced in the small intestine and colon of germ-free and conventional rats treated with intrarectal 1,2-dimethylhydrazine; the number of rats with colon tumors and the multiplicity of tumors were decreased in germ-free rats, compared with conventional animals. Azoxymethane given subcutaneously increased the incidence and multiplicity of colon tumors in germ-free rats, compared with conventional controls. It is concluded that the intestinal microflora alter the carcinogenic and/or cocarcinogenic effect of different compounds in the large intestine.

Animals↗
PubMed1992

Folate deficiency enhances the development of colonic neoplasia in dimethylhydrazine-treated rats.

In patients with ulcerative colitis, epidemiological work has suggested an association between low folate status and an increased risk of colonic neoplasia. The aim of the present study was to determine if experimental folate deficiency increases the likelihood of developing neoplasia in rats treated with the carcinogen dimethylhydrazine. Weanling male Sprague-Dawley rats were fed with an amino acid-defined diet containing either 8 or 0 mg/kg folic acid. After 5 weeks of defined diet, weekly s.c. injections of dimethylhydrazine (20 mg/kg) were administered to both groups. Serum, whole blood, liver, and colonic folate concentrations at the time of sacrifice were significantly lower in folate-depleted animals (P less than 0.001). There were significant differences in the incidence of colonic neoplasia between the two groups after 20 weeks of dimethylhydrazine exposure: folate-deficient rats had a greater incidence of dysplasia (6 of 7 versus 2 of 7 animals; P less than 0.05) and carcinoma (6 of 7 versus 1 of 7 animals; P less than 0.01). Furthermore, a significantly greater proportion of folate-replete rats than folate-deficient rats were free of neoplastic lesions (5 of 7 versus 0 of 7 animals; P less than 0.05). These results suggest that, in this animal model, folate deficiency increases the risk of malignancy when there is an underlying predisposition to colorectal cancer.

Animals↗
PubMed1991

DNA aneuploidy and proliferation in spontaneous human and dimethylhydrazine-induced murine colorectal carcinogenesis.

DNA aneuploidy and proliferative abnormalities were studied by flow cytometry in 169 colorectal specimens from 162 patients. Of 37 adenomas, three showed aneuploidy and another seventeen revealed a "near diploid" DNA pattern. The rate of aneuploid and "near diploid" DNA changes in 92 carcinomas was 53.3% and 23.9%, respectively. No correlation was seen between the ploidy distribution and the stage or histologic grade of the carcinomas. The S-phase fractions of both adenomas and carcinomas significantly increased from the diploid (8.1 +/- 0.8% and 7.8 +/- 0.9% respectively; mean +/- SEM) to the "near diploid" (14.9 +/- 1.2% and 12.6 +/- 1.5%) and aneuploid (20.4 +/- 1.3% and 11.4 +/- 1.6%) lesions. To better understand neoplastic progression at very early stages, flow cytometry was also performed on 195 colonic specimens of 44 rats treated by weekly subcutaneous injections of 21 mg/kg Dimethylhydrazine. There was a single "near diploid" carcinoma in this group, and all other induced neoplasms (39 carcinomas and 27 adenomas) revealed a diploid DNA pattern. The S-phase fractions were as follows: controls (38 untreated animals) 8.6 +/- 0.1%, normal mucosa (of Dimethylhydrazine exposed rats) 10.1 +/- 0.25% (p less than 0.0001), adenomas 13.9 +/- 0.6% (p less than 0.01), and carcinomas 14.7 +/- 0.6% (p less than 0.01). These findings support the conclusion that genomic alterations and proliferative abnormalities may already be present in premalignant human colonic lesions. However, despite strong morphological similarities, major biological differences exist between the Dimethylhydrazine-induced murine intestinal carcinogenesis and spontaneously occurring human colorectal neoplasms.

Adolescent↗
PubMedDate not supplied

Inhibition of 1,2-dimethylhydrazine metabolism by disulfiram.

1. The effects of disulfiram on the metabolism of 1,2-dimethylhydrazine were studied in CDF rats. 2. Treatment with disulfiram causes enhanced elimination of azomethane in the expired air, inhibition of CO2 production, and decreased levels of 1,2-dimethylhydrazine metabolites in the urine. 3. These results suggest that disulfiram inhibits the N-oxidation of azomethane to azoxymethane, thus preventing further metabolism to the ultimate carcinogenic species, and provide an explanation for the observations that disulfiram inhibits 1,2-dimethylhydrazine-induced neoplasia of the large intestine.

Animals↗
PubMed1975

Colon carcinogenesis with azoxymethane and dimethylhydrazine in germ-free rats.

The effect of intestinal microflora on the sensitivity of the colon to the carcinogenic effect of azoxymethane and a large dose of 1,2-dimethylhydrazine was studied using germ-free and conventional female Fischer rats. Injection s. c. of 1,2-dimethylhydrazine-induced tumors of the ear duct, kidney, and small intestine of conventional rats but none in germ-free animals. Only 20% germ-free rats showed 1,2-dimethylhydrazine-induced colonic tumors, whereas 93% of conventional rats developed multiple colonic tumors. Intrarectal instillation of azoxymethane appreciably increased the multiplicity of colonic tumors in germ-free rats and in gnotobiotic rats contaminated with Clostridium perfringens, as compared to conventional controls. None of the germ-free rats showed ear duct tumors. The incidence of kidney tumors was lower in germ-free rats than in other groups. It is concluded than the intestinal microbial populations alter the effect of carcinogens in the large intestine.

Adenocarcinoma↗
PubMed1991

Characterization of cytochrome P450-dependent dimethylhydrazine metabolism in human colon microsomes.

Polyclonal antibodies to components of the rat liver cytochrome P450 system were used to examine the composition and function of the microsomal cytochrome P450-dependent monooxygenase system of human colonic mucosal cells. Anticytochrome P450 reductase antibody gave a strong band of immunocross-reactivity in human colon microsomes at the same molecular weight level as purified cytochrome P450 reductase from rat liver, as well as hepatic microsomes isolated from untreated or phenobarbital-treated rats. These results demonstrate the presence of cytochrome P450 reductase in human colon cells. Similarly, cytochromes P450 IIB1 and IIA1 also appear to be present in Western blots of human colon microsomes. These antibodies, as well as antibodies to reductase and cytochrome b5, inhibit dimethylhydrazine metabolism in human colon microsomes to varying degrees. These data argue for a functional P450-dependent drug metabolism system in colon capable of activating/metabolizing the colon-specific model carcinogen, 1,2-dimethylhydrazine.

1,2-Dimethylhydrazine↗