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At least 19 recordsLinked to original sources
PubMed1976

Cell proliferation in the descending colon of dimethylhydrazine treated rats and in dimethylhydrazine induced adenocarcinomata.

A stathmokinetic technique which has estimable precision has been used to estimate mitotic rates in the crypts of Lieberkühn in the descending colon of normal, and of dimethylhydrazine (DMH)-treated rats, as well as in DMH-induced adenocarcinomata. Estimates of the mean number of proliferating and of non-proliferating cells per crypt of Lieberkühn were also made in normal and in DMH-treated rats. In normal rats, epithelial cell proliferation was found to be relatively slow in the basal one-fifth of the crypts of Lieberkühn and to be most rapid in the second one-fifth of the crypt. In DMH-treated rats the number of cells around the circumference of transversely sectioned crypts was significantly increased, as was the number of proliferating cells present in longitudinally sectioned crypts. The region of relatively slow cell proliferation in the base of the crypts was expanded to occupy the lower two-fifths of the crypt in DMH-treated rats whilst the region of most rapid cell proliferation was displaced upwards to occupy the third one-fifth of the crypt. In DMH-induced adenocarcinomata cell proliferation occurred at a rate similar to that in the relatively quiescent zone at the bases of the colinic crypts in normal animals. However, tumour cell proliferation was substantially slower than that in the second one-fifth of the crypt in normal animals.

Adenocarcinoma↗
PubMed1975

Autoradiographic studies on the distribution of 14C-1,2-dimethylhydrazine dihydrochloride and its effect on DNA synthesis in Swiss mice.

Light microscopic autoradiographic studies were made on the distribution of 14C-1,2-dimethylhydrazine dihydrochloride in Swiss mice and on the effect of 1,2-dimethylhydrazine dihydrochloride on DNA synthesis, using the 3H-thymidine incorporation technique. In the first study, 14C-1,2-dimethylhydrazine dihydrochloride was administered subcutaneously or orally. Large amount of silver grains were found in hepatocytes and substantially lower amount of silver grains observed in the endothelial cells and epithelial cells of colon. In the second study, repeated injections or oral administrations of 1,2-dimethylhydrazine dihydrochloride were given to mice which subsequently received 3H-thymidine treatment. A somewhat higher amount of thymidine incorporation in DNA was noted in the epithelial cells of the colon of subcutaneously and orally treated mice at two occasions and a substantially higher amount in the endothelial cells of blood vessels in liver of mice treated by both routes than in the corresponding controls. In three instances, however, the amount of incorporation decreased; in the hepatocytes and endothelium at 1 week and 24 hr, respectively, after oral treatment, and in the epithelium of the colon at 3 months, after subcutaneous administration. In the mice treated with 1,2-dimethylhydrazine dihydrochloride, a significantly high amount of 3H-thymidine incorporation was observed in the endothelial cells of blood vessel in liver from which tumors later arose, and somewhat high in the hepatocytes in which tumor did not develop. In the epithelial cells of colon, no apparent relationship can be seen between these events. No association was seen in the distribution of 14C-1,2-dimethylhydrazine dihydrochloride and tumor development in various cells.

Administration, Oral↗
PubMed1992

Alterations in protein kinase C in 1,2-dimethylhydrazine induced colonic carcinogenesis.

Protein kinase C activity and the profile of protein kinase C isozymes alpha, beta, and gamma were examined in subcellular fractions of 1,2-dimethylhydrazine induced colonic adenocarcinomas, surrounding uninvolved colonic mucosa and colonic mucosa from age matched control rats. Responsiveness of colonic mucosal protein kinase C to phorbol dibutyrate induced translocation of the enzyme from the soluble to the particulate cell fraction was also assessed. Although total protein kinase C and specific activities of soluble and particulate enzymes were higher in colonic mucosa of carcinogen treated rats which developed tumors than corresponding values of control mucosa, the subcellular distribution of enzyme activity was not different between uninvolved colonic mucosa of 1,2-dimethylhydrazine treated rats and colonic mucosa of age matched control rats. Thus, evidence for activation of the protein kinase C system of mucosa of the carcinogen treated rats was lacking. Exposure of colonic mucosa from control rats to phorbol dibutyrate induced a clear translocation of enzyme activity from the soluble to the particulate fraction. By contrast, no change in subcellular distribution of protein kinase C activity was noted on exposure of colonic mucosa from 1,2-dimethylhydrazine treated rats to phorbol dibutyrate. Immunoblotting of subcellular fractions of colonic mucosa from control and 1,2-dimethylhydrazine treated rats demonstrated the presence of protein kinase C alpha, but no detectable beta and gamma forms. Total protein kinase C activity and the specific activity of protein kinase C in soluble and particulate fractions was significantly lower in adenocarcinomas compared to uninvolved surrounding mucosa. In contrast to results obtained with colonic mucosa from control and 1,2-dimethylhydrazine treated rats, adenocarcinomas expressed predominantly the beta form of protein kinase C. The alpha form represented less than 10% of the total detectable immunoreactivity in adenocarcinomas. The alterations in protein kinase C isoenzyme expression in tumors and loss of responsiveness of premalignant mucosa to phorbol dibutyrate may be involved in the process of malignant transformation.

1,2-Dimethylhydrazine↗
PubMed1976

Early effects of a single intrarectal dose of 1,2-dimethylhydrazine in mice.

The early morphological and biochemical effects of intrarectally administered 1,2-dimethylhydrazine dihydrochloride on mouse colon were studied. Using [3H]thymidine autoradiography, it was found that 1,2-dimethylhydrazine dihydrochloride, 250 mg/kg decreased the number of prelabeled DNA-synthesizing cells in the distal colon as early as 30 min after instillation. During the interval from 24 hr to 2 weeks, however, the opposite effect was seen; incorporation of [3H]thymidine increased 3- to 5-fold over controls. At lower doses (0.25 to 25 mg/kg), a similar trend was observed. Histological examination showed no dramatic changes in cell structure or in tissue architecture. No changes were seen in labeling indices in the proximal colon. In the liver, cellular alterations were seen at concentrations of 25 to 250 mg/kg, particularly in the centrolobular region. These changes were evident at 2 hr and disappeared by 4 hr. The kidney was unaffected by 1,2-dimethylhydrazine dihydrochloride at any concentration. Our results suggest that enzymes capable of activating 1,2-dimethylhydrazine dihydrochloride are located within the mucosal cells of the distal colon.

Animals↗
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↗
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↗
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↗
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↗
PubMed1977

Alterations in fecal microflora enzymes related to diet, age, lactobacillus supplements, and dimethylhydrazine.

The bacterial enzymes, beta-glucuronidase, azoreductase, and nitroreductase, have been measured in the fecal microflora of rats. The effects of diet, advanced age, Lactobacillus acidophilus supplements, and dimethylhydrazine on these microbial enzymes activities have been determined. The shift from a grain to a meat diet resulted in 1.5--2.5-fold increase in the activity of all three enzymes. Animals over 20 months of age, consuming a meat diet, showed further increases in fecal beta-glucuronidase activity, while the levels of all three microbial enzymes increased in old rats fed a grain diet. Feeding supplement of L. acidophilus significantly lowered the activity of fecal nitroreductase and azoreductase in meat-eating animals, but had no effect on nitroreductase activity in grain-fed animals. Dimethylhydrazine increased the fecal beta-glucuronidase activity in both grain- and meat-fed animals, but the carcinogen had no effect on nitroreductase or azoreductase activity. These findings have relevance to known features of the epidemiology and etiology of large bowel cancer, and suggest certain approaches to prevention.

Aging↗
PubMed1977

Investigations into the metabolism and mode of action of the colon carcinogens 1,2-dimethylhydrazine and azoxymethane.

Colon cancer can be induced reliably in rodents with 1,2-dimethylhydrazine and azoxymethane (AOM). Our studies deal with the mode of action of these compounds and their organotropism. A partial summary of our previous work on the metabolism of 1,2-dimethylhydrazine and its inhibition by disulfiram, carbon disulfide and other thiono-sulfur compounds is presented. On-going studies with AOM-14C indicate that in male F-344 rats, this carcinogen is rapidly metabolized to 14CO2 (37%, 48 hours), and to methylazoxymethanol-14C (MAM) (0.6--1%), which, along with other metabolites, appears in the urine. Pretreatment of rats with phenobarbital or chyrsene increased exhaled 14CO2 to 53% and 65%, respectively. Pretreatment with disulfiram or CS2 causes a complete, although transient, inhibition of exhaled 14CO2, decreases urinary MAM, and increases significantly the levels of unmetabolized AOM in the exhaled air and in urine. Thus, phenobarbital and chrysene appear to stimulate, while disulfiram and CS2 appear to inhibit, the metabolism of AOM. In vitro hydroxylation of AOM to MAM was demonstrated with rat liver homogenates and microsomal fractions. A hypothetical scheme for the endogenous formation of AOM is presented.

Animals↗
PubMed1978

Inhibition of the alkylation of nucleic acids and of the metabolism of 1,2-dimethylhydrazine by aminoacetonitrile.

Pretreatment of rats with aminoacetonitrile inhibited the metabolism of [14C]1,2-dimethylhydrazine to 14CO2 and increased the expiration of [14C]-azomethane. Alkylation of nucleic acids following administration of 1,2-dimethylhydrazine was reduced by aminoacetonitrile to 5% of control levels in liver, 11% of control levels in kidney and 43% of control levels in colon.

Acetonitriles↗
PubMed1976

Separation of 1,2-dimethylhydrazine metabolites by high-pressure liquid chromatography.

The separation of 1,2-dimethylhydrazine, azomethane, azoxymethane, methylazoxymethanol, methylazoxymethanol acetate, formaldehyde and methanol by high-pressure liquid chromatography on columns of C18/Corasil, muBondapak C18 and Aminex A-27 is described. The separations are highly reproducible and rapid and may be used for kinetic studies. An example of an application of these methods to the analysis of metabolites in rat urine derived from (14C)-1,2-dimethylhydrazine is reported.

Animals↗
PubMed1977

Dimethylhydrazine-induced colon tumors in rats fed diets containing beef fat or corn oil with and without wheat bran.

Male rats of the Sprague-Dawley strain were fed semisynthetic diets containing either 20% beef fat or corn oil with and without 20% wheat bran. Half of the animals received four weekly doses and the other half received eight weekly doses of dimethylhydrazine, 30 mg/kg, by intragastric intubation. The percentage of rats with tumors of the colon of all types was significantly higher in animals fed no bran than in those fed bran. Likewise, the percentage of rats with polypoid neoplasms of the colon was higher in rats fed no bran, but there was no significant difference in the percentage of rats with malignant tumors of the colon with respect to the feeding of bran. No significant differences were found between rats fed corn oil and those fed beef fat with respect to either the incidence or the kinds of colon tumors. Malignant tumors of the colon, causing death, occurred earlier in rats fed corn oil as compared to those fed beef fat. The percentage of rats with tumors of the colon and the numbers of tumors per tumor-bearing rat were significantly increased in rats given eight doses of dimethylhydrazine or compared to those given four.

Adenocarcinoma↗
PubMed1978

Effect of hydrazine, isonicotinic acid hydrazide, hydrazine sulfate, and dimethylhydrazine on guanylate cyclase activity.

The chemical carcinogen hydrazine is a potent stimulator of guanylate cyclase. In the present investigation we found that three chemical carcinogens structurally related to hydrazine, isonicotinic acid hydrazide, hydrazine sulfate, and dimethylhydrazine, decreased guanylate cyclase activity. It is of interest that hydrazine has been shown to increase DNA synthesis whereas isonicotinic acid hydrazide, hydrazine sulfate, and dimethylhydrazine decrease DNA synthesis. The relationship, if any, linking the guanylate cyclase-cyclic GMP system to DNA synthesis and carcinogenesis remains to be explored.

Animals↗
PubMed1976

Histogenesis and growth pattern of 1,2-dimethylhydrazine-induced rat colon adenocarcinoma.

The histogenesis and growth pattern of colon adenocarcinoma have been studied using 74 BD IX rats given 20 mg 1,2-dimethylhydrazine hydrochloride per kg, s.c., weekly from Day 11 to their 24th week and serially sacrificed with controls. Modifications in DNA synthesis activity and early tumor changes were sought on histological and radioautographic preparations of normal-appearing colon mucosa. All visible colorectal tumors were analyzed for size, site, and pathology. Chronic dimethylhydrazine treatments resulted in a simultaneous increase in the number of both total and tritiated thymidine-labeled cells in the glands of Lieberkühn. In addition, microscopic carcinomatous foci were observed after the 15th week, and the first macroscopic adenocarcinomas appeared in 24-week-old animals. Their number thereafter exponentially increased with time. A total of 252 macroscopic tumors were obtained, of which 14 were classified as signet ring cell carcinomas and 238 as adenocarcinomas. Among the latter, local invasion could be documented in 230, including the smallest. No benign polypcancer sequence could be demonstrated in this material. The average growth pattern of those adenocarcinomas could be adequately described by a Gompertz curve, with a short initial doubling time (e.g., 7.5 days in 1.0-cu mm tumors) that progressively increases with time (e.g., 59.6 days in 5000-cu mm tumors).

Adenocarcinoma↗
PubMed1979

Protective effect of oral Salmonella enteritidis 11RX infection against colon tumor induction by 1,2-dimethylhydrazine in mice.

Infection of mice with Salmonella enteritidis 11RX has been shown previously to cause nonspecific immune stimulation and, consequently, resistance to subsequent challenge with a variety of transplantable tumors. The present study has examined the effect of infection with this organism in a chemical carcinogenesis system. Colonic tumors were induced in LACA and BALB/c x C57BL/6JF1 mice by weekly s.c. injection of 1,2-dimethylhydrazine (15 mg/kg) for 28 weeks. Infection of mice p.o. with live S. enteritidis 11RX at 8-week intervals during 1,2-dimethylhydrazine administration protected both strains against colon tumorigenesis. Significantly fewer infected than control BALB/c x C57BL/6JF1 mice had colonic tumors at or before termination of the experiment (34 or 40 weeks) (p less than 0.001 in all cases). Comparable results were obtained with both male and female mice. The difference in tumor incidence between control and infected LACA mice was not statistically significant, however; the number and size of the lesions was greater in control mice (p less than 0.02). Although it has not been proven that the protective effect is mediated by the immune system, the results are consistent with the operation of a macrophage-mediated surveillance system. It is suggested that enteric infections should be considered as a possible contributing factor in the epidemiology of human colonic cancer.

Adenocarcinoma↗