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PubMed1985

Immunohistologic analysis of the T-cell and macrophage infiltrate in 1,2-dimethylhydrazine-induced colon tumors in the rat.

The infiltrating mononuclear cell (MNC) type, and the localization of major histocompatability class I and class II antigens within 1,2-dimethylhydrazine (CAS: 540-73-8)-induced colonic tumors and normal colonic mucosa in WF/Hsd BR rats were investigated by immunoperoxidase staining of frozen sections with the use of monoclonal antibodies. Infiltrating T-cells stained with monoclonal antibodies W3/13, W3/25, and MRC OX 8; W3/13+ cells were predominant. The most numerous and consistently observed infiltrating cell type was an la antigen-bearing (MRC OX 6+, MRC OX 17+) macrophage. A smaller subpopulation of macrophages, staining with W3/25, showed a similar distribution within tumors. In adenomas and in some well-differentiated adenocarcinomas, the infiltrating MNC were concentrated at the tumor periphery and were in close proximity to neoplastic epithelia, but without evidence of consequent tumor cell necrosis. In all other tumors, infiltrating host cells were confined to the connective tissue stroma dividing clusters of neoplastic glands. The extent of cellular infiltration and the phenotypes of infiltrating cells did not correlate with the degree of tumor differentiation or with tumor size. Expression of MHC class I antigens (MRC OX 18) by tumor cells did not differ from that of normal epithelia, and neoplastic epithelia were uniformly negative for class II antigens (MRC OX 6, MRC OX 17). The data do not support a role for cytotoxic macrophages or T-cells in the local response to colon tumors.

1,2-Dimethylhydrazine↗
PubMed1985

[Immunomorphological study of 1,2-dimethylhydrazine-induced carcinomas of the large intestine in rats using monoclonal antibodies to intermediate filament proteins].

Cryostatic sections of rat large bowel tumors induced by 1,2-dimethylhydrazine were stained with monoclonal antibodies against different proteins of intermediate filaments: (a) against prekeratin (mol. mass 49 000, PK49) found in many epithelial cells and (b) against vimentin, a constituent of intermediate filaments of mesenchymal cells. Immunofluorescence study showed that large bowel tumor cells as well as normal cells of this organ contain PK49 but not vimentin. High sensitivity of the method allowed one to clearly identify small invasive nodules and groups of tumor cells not visible in usual histologic preparations. Moreover, in some cases single atypical tumor cells were identified in tumor stroma and in the submucosal layer underlying the tumor, that were indistinguishable from normal mesenchymal cells at the light microscopy level.

1,2-Dimethylhydrazine↗
PubMed1985

Longer survival and fewer metastases by levamisole and tegafur in 1, 2-dimethylhydrazine-induced murine colonic cancers.

The anticancer effects of levamisole, tegafur and their combination were experimentally compared in rats on the 1, 2-dimethylhydrazine (DMH)-induced colonic cancers. DMH at 20 mg/kg of body weight was injected subcutaneously to Donryu rats once a week for 24 weeks long. Nineteen weeks after the start of DMH administration, early colonic cancers were induced and, 28 weeks after, they developed into advanced cancers with distant metastases. From 19 weeks after the start of DMH injection, subcutaneous administration of levamisole at the dose of 2 mg/kg, oral administration of tegafur at 90 mg/kg and their combination were given to the rats daily for nine weeks. The animals were sacrificed 28 weeks after the start of DMH administration. Tegafur was effective, but levamisole with or without tegafur was not effective against early cancer. From 28 weeks after the start of DMH injection, levamisole, tegafur and their combination were administered to the rats daily for four weeks. All of the rats were necropsied when they died. The survival rate and mean survival days were significantly higher and longer in the levamisole groups than in the control rats (p less than 0.05). The incidence of distant metastases was also significantly lower in the levamisole groups than in the control group.

1,2-Dimethylhydrazine↗
PubMed1986

[Proliferative activity of the uterine epithelium and mesenchymal elements in CBA-strain mice administered 1,2-dimethylhydrazine and estradiol dipropionate].

Difference have been demonstrated in proliferative responses of epithelial and mesenchymal cells in the uterus of CBA mice under administration of 20 weekly subcutaneous injections of 1,2-dimethylhydrazine (DMH) and estradiol dipropionate (EP) separately and in combination (DMH+EP). The proliferative pool (Pc) of uterine glands epithelium increases under the effect of EP and decreases under the effect of both DMH and DMH+EP. The proliferative pool of mesenchymal cells increases under the effect of DMH, EP, and DMH+EP 5 to 10 weeks after the beginning of their administration, then it decreases. But percentage of DNA synthesizing cells in the regions of hyperplasia and the tumour formation enhances significantly by the 15th to 20th weeks after the beginning of DMH+EP administration.

1,2-Dimethylhydrazine↗
PubMed1986

[Effect of sex hormones on the 1,2-dimethylhydrazine metabolic activity in the kidneys of CBA-strain mice].

1,2-dimethylhydrazine (DMH) metabolizing activity of kidney microsomes was shown to be two times higher in male, than in female CBA mice. Castration decreased DMH metabolizing activity of male kidney microsomes to the females' level. DMH metabolizing activity of castrated males treated with testosterone propionate was identical to that of intact males. The incorporation of 14C-DMH into kidney DNA was also higher in male, than in female CBA mice.

1,2-Dimethylhydrazine↗
PubMed1985

[Modifying action of neonatal androgenization on 1,2-dimethylhydrazine-induced carcinogenesis in male CBA-strain mice].

Newborn male CBA mice received a single treatment with 0.5 mg testosterone propionate. Weekly subcutaneous injections of 1,2-dimethylhydrazine (DMH) were given to 2-month-old mice. The incidence of pararenal angiosarcomas and colonic tumors in neonatally androgenized mice reached 78.5 and 71.0%, respectively by the 35th week after the DMH treatment was commenced. In DMH-treated control mice, the incidence of the above tumors amounted to 25 and 32%, respectively.

1,2-Dimethylhydrazine↗
PubMed1985

Changes in tissue and serum activity of cathepsin B-like cysteine proteinase during colorectal carcinogenesis by 1,2-dimethylhydrazine in mice.

The activity of cathepsin B-like cysteine proteinase in the mice colon was studied during carcinogenesis induced by 1,2-dimethylhydrazine dihydrochloride (DMH). Before starting the treatment with DMH, the activity of the observed enzyme was very low in the colorectal area but the activity in the serum was rather high. In the course of carcinogenesis, the local activity markedly increased in the stroma equally as in the cells of developing tumors while the serum activity slightly decreased. Following the total ovariectomy, no significant changes in the local activity or in the serum activity were found. Possible causes of these variations are discussed.

1,2-Dimethylhydrazine↗
PubMed1985

[Development of 1,2-dimethylhydrazine-induced colonic neoplasia in rats and changes in cellular proteins of colonic mucosa].

Development of 1,2-dimethylhydrazine (DMH) induced colonic neoplasia were studied using male Wistar rats given 120 mg DMH per kg s.c. weekly for 5 weeks. During the course of colon carcinogenesis, changes in cellular proteins of colonic mucosa were analysed by two-dimensional gel electrophoresis. Rats were sacrificed just before and at 10, 15 and 20 weeks after the initial DMH treatment together with controls. Incidence and number of colorectal tumors gradually increased. At the 20th week, colon carcinoma was found in every rat. Most tumors (92%) were found in the major flexure and the distal colon and rectum, while only 1% and 7% were found in the cecum and proximal colon, respectively. Histologically, most (92%) were classified as well differentiated or moderately differentiated adenocarcinoma. Eighty-five percent of the tumors were semipedunculated or sessile without depression, and the remainder were sessile with depression. All of the latter were carcinomas with invasion to the submucosa or further. Two-dimensional gel electrophoresis revealed 180 spots in cellular proteins before and after the initial treatment. Three new spots appeared and four spots greatly increased during the course of carcinogenesis, while one spot disappeared. The above results suggest that the appearing and increasing spots may be associated with cancer and that the disappearing spot may be associated with the normal colon.

1,2-Dimethylhydrazine↗
PubMed1981

[Neuropharmacologic regulation of the carcinogenic action of 1,2-dimethylhydrazine].

Chronic experiments were made on 100 male rats to examine the modifying effects of adrenergic and cholinergic agents that regulate homeostasis on 1,2-dimethylhydrazine-induced intestinal carcinogenesis. The sympatholytic guanethidine (5 mg/kg) and the alfa-adrenoblocker butyroxan (2.5 mg/kg) did not influence the carcinogenesis in the intestine. The noradrenaline- and atropine-induced (1 mg/kg and 10 mg/kg) increase in the adrenergic component of the vegetative nervous system led to the decrease in the number (by 2-3 times) and size of the tumor nodes in the intestine. The drugs did not affect the morphology of neoplasms. The results are discussed in terms of essential importance of the vegetative nervous system in the mechanism of chemical carcinogenesis.

1,2-Dimethylhydrazine↗
PubMed1983

Enhancing effect of dextran sulfate sodium on colorectal carcinogenesis by 1,2-dimethylhydrazine in rats.

Four groups were used, each consisting of 24 male ACI rats. Group I received a single subcutaneous injection of 20 mg 1,2-dimethylhydrazine (DMH)/kg body weight and was fed on basal diet until the termination of the experiment. Group II received the same single injection as in group I and then, starting one week later, was fed the diet containing 1% dextran sulfate sodium (DS-M-1). Group III received an injection of 0.9% sodium chloride and then DS-M-1 diet. The control group was given neither DMH nor DS-M-1 diet. The experiment was terminated after 40 weeks. A significantly higher incidence of colorectal carcinoma was observed in group II, as compared with group I (P less than 0.02). These data demonstrate the enhancing effect of DS-M-1 on colorectal carcinogenesis.

1,2-Dimethylhydrazine↗
PubMed1983

Enhancement of rat colon carcinogenesis by wheat bran consumption during the stage of 1,2-dimethylhydrazine administration.

The effect on intestinal carcinogenesis 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 31 weeks. Nutrient intake and body weight gain were equivalent in all groups of animals. In the rats fed bran during carcinogen administration, tumor yield was significantly greater. Benign and malignant tumors increased by 3.4-fold (p less than 0.005), adenomas by 3.5-fold (p less than 0.025), and adenocarcinomas by 3.25-fold (p less than 0.05) over the yield found in the group fed a fiber-free diet. Consumption of wheat bran, after completion of carcinogen exposure, reduced the yield of benign adenomas by 71.4% when compared with the group fed the fiber-free diet (p less than 0.025). Those rats fed a wheat bran supplement during carcinogen administration and then switched to a fiber-free diet afterwards had the highest tumor yield, 4.5 times as many benign and malignant tumors as in those rats consistently fed the fiber-free diet (p less than 0.05) and at least 6 times as many adenomas as any of the other dietary groups (p less than 0.05). These results demonstrate that dietary wheat bran, a fiber which produces a hyperproliferative response in the colon, significantly increases colon carcinogenesis when fed to rats during the stage of carcinogen administration. This effect appears to be further enhanced when the wheat bran is totally removed from the diet following the stage of carcinogen administration. These data indicate that the hyperproliferative effects of wheat bran appear to outweigh any preventive actions that bran may have on colon carcinogenesis by altering the bulk of intestinal contents and their transit time through the bowel.

1,2-Dimethylhydrazine↗
PubMed1983

Effect of dietary protein concentration on yield of mutagenic metabolites from 1,2-dimethylhydrazine in mice.

The effects of varying dietary protein concentrations on the metabolism of 1,2-dimethylhydrazine (DMH) to mutagenic products by male C57BL/6 X C3H F mice were assayed by in vivo and in vitro methods. DMH and its metabolite, azoxymethane (AOM), did not increase the mutation frequency of Salmonella typhimurium (strain G-46) in vitro alone or in the presence of mouse liver homogenates capable of activating the promutagen dimethylnitrosamine. Methylazoxymethanol (MAM), another metabolite of DMH, was mutagenic in vitro without activation. S.c. administration of DMH, AOM, or MAM at dosages ranging from 0.2 to 0.8 mmol/kg of body weight caused dose-dependent increases in mutations of S. typhimurium in the host-mediated assay, and molar potencies increased progressively from DMH to AOM to MAM. S.c. or i.p. injections of AOM increased host-mediated mutagenesis within 20 min, while increases in mutagenesis by DMH required at least 1 hr. When [14C]DMH was administered, [14C]azomethane was expired immediately, while 14CO2 began to appear 1 hr after DMH administration. The percentage of administered [14C]DMH expired as azomethane varied inversely with dietary protein concentration, while AOM-induced host-mediated mutagenesis was directly proportional to dietary protein (p less than 0.01). The percentage of DMH converted to mutagenic end products was limited by losses of the volatile metabolite azomethane, especially in protein-deficient mice. Greater expiration of azomethane and decreased conversion of AOM to MAM, both seen with restriction of dietary protein, were associated with a smaller body burden of DMH metabolites.

1,2-Dimethylhydrazine↗
PubMed1983

Inhibition of ornithine decarboxylase with 2-difluoromethylornithine: reduced incidence of dimethylhydrazine-induced colon tumors in mice.

2-Difluoromethylornithine (DFMO) was administered to 1,2-dimethylhydrazine (DMH)-treated mice to reduce colonic polyamine levels and mucosal hyperplasia. Mice received 1% DFMO in drinking water throughout the experiment and were given injections of DMH (20 mg/kg) weekly for 28 weeks. DFMO inactivated 93% of colonic ornithine decarboxylase activity. Although DMH treatment did not induce colonic ornithine decarboxylase activity by Week 28, the putrescine content was increased 31% in DMH-treated mice (p less than 0.01). Concurrent treatment with DFMO depressed putrescine content (42 to 63%) and spermidine content (27 to 38%), but it increased spermine content (18 to 22%). At Week 28 of treatment with DMH alone, RNA content was increased 8.6% (p less than 0.01), DNA content 10% (p less than 0.01), DNA specific activity 24% (p less than 0.01), and crypt depth 20% (p less than 0.01), but not in mice receiving DMH and DFMO. At 28 weeks, 13 of 17 mice (76%) treated with DMH alone had histologically confirmed colon cancers; of mice treated with DMH and DFMO, two of 18 (11%) had colonic tumors. Throughout the experiment, 50 colon cancers developed in 16 DMH-treated mice (mean, 3.12 tumors/mouse); three mice treated with DMH and DFMO developed three colon cancers total (p less than 0.001). Reduction of colonic polyamine levels after DFMO treatment prevents proliferative changes induced by DMH and reduces the incidence of tumors.

1,2-Dimethylhydrazine↗
PubMed1984

[Changes in the cytoskeleton and surface charge as a possible cause of the increased mechanical binding between enterocytes in the small intestine epithelium induced by 1,2-dimethylhydrazine].

Alterations in the mechanical linkage between the enterocytes in BALB/c mouse colonic epithelium were investigated under the influence of agents affinitable to the cell surface and cytoskeleton. It is found that cytochalasin B (10(-6) - 10(-5) g/ml), low pH (pH 3) and low concentration of colchicine (10(-8) g/ml) increased, but EDTA (5 X 10(-3) g/ml) and high concentration of colchicine (10(-4) g/ml) reduced the magnitude of mechanical linkage between the enterocytes. A comparative analysis of the data obtained with the control and with 1,2-dimethylhydrazine (DMH) treated mice indicates that probable reasons of a DMH-induced rise in the intercellular mechanical linkage may involve the decrease in electrostatic repulsive forces between the cell surfaces, and the weakening of centripetal tensions due to a decrease in negative surface charge and disorganization of the microfilament system, respectively. These alterations of the cell surface negative charge and the cytoskeleton are expressed on day 3 after a single injection of DMH and are seen to persist during repeated carcinogen applications.

1,2-Dimethylhydrazine↗
PubMedDate not supplied

Steroid hormone receptors in dimethylhydrazine-induced rat colonic tumors.

The presence of steroid hormone receptors was investigated in rat colonic tumors, experimentally induced by 1,2-dimethylhydrazine, and in adjacent normal tissues. Estrogen, progesterone, glucocorticoid, and 5-alpha-dihydrotestosterone receptor levels were measured by the dextran charcoal competitive binding assay. Estrogen receptors were present in 25% of tumors, although not in adjacent normal tissue. Higher levels of glucocorticoid binding in tumor versus adjacent normal tissue were demonstrated in 5 out of 8 cases. Progesterone and 5-alpha-dihydrotestosterone levels in tumor versus adjacent normal tissue were not significantly different. The results reflect the possible endocrine dependence of colonic tumors.

1,2-Dimethylhydrazine↗
PubMed1984

The effect of promoters on 1,2-dimethylhydrazine-induced colon carcinogenesis.

The influence of 12-O-tetradecanoylphorbol 13-acetate (TPA) and vincristine (VCR) on the development of colon carcinoma induced by 1,2-dimethylhydrazine (DMH) has been studied by light and electron microscopy. The ability of TPA to induce the appearance of cells with a heterogeneous genotype has been investigated by cytophotometric evaluation of DNA content. The TPA-induced phenotypic alterations have been studied by quantitative histochemistry. The influence of promoters on the outcome of DMH-induced carcinogenesis has been investigated in DMH-resistant C57 Black mice. Aneuploid DNA populations were detected in hyperplasias induced by DMH or TPA; in carcinomas, the percentage of hyperdiploid cell populations was further increased. DNA aneuploidy is defined as the genetic instability of cells that can be induced by TPA treatment alone. TPA can induce dedifferentiation of hyperplastic cells, as demonstrated by quantitative histochemistry of the intestinal mucins. TPA increased the colon tumour incidence in DMH-resistant C57 Black mice. A promoter-like action of VCR could also be observed.

1,2-Dimethylhydrazine↗
PubMed1983

Methylated DNA adducts in the large intestine of ICR/Ha and C57BL/Ha mice given 1,2-dimethylhydrazine.

The site-specific incidence of 1,2-dimethylhydrazine (DMH)-induced neoplastic changes in intestinal segments of ICR/Ha mice correlates with the persistence of O6-methylguanine (O6MGua) after a single carcinogen injection. Six hours after the injection, the amount of O6MGua in four anatomic (proximal to distal) segments was 16.0, 20.8, 37.5, and 52.8 mumol/mol guanine, respectively. Correlation between the incidence of neoplasms and the amount of alkylation was also observed 14, 40, and 96 hours after DMH treatment. Similar levels of O6MGua were found in the corresponding colon segments of C57BL/Ha mice. After repeated treatment (5 wk) with unlabeled DMH, the amount of O6MGua still correlated with the incidence of neoplasms in ICR/Ha mice. However, in each strain the level of O6MGua was significantly lower in pretreated mice than in mice without DMH pretreatment. Furthermore, the amount of adducts in DNA isolated from different crypt depths showed that within a few hours of the DMH injection the amount of adducts was independent of DNA synthetic activity. Although ICR/Ha and C57BL/Ha mice have different susceptibility to DMH-induced colon cancer, this interstrain difference is not reflected in the amounts or persistence of the miscoding base O6MGua.

1,2-Dimethylhydrazine↗
PubMed1983

Enhancing effect of vitamin E on murine intestinal tumorigenesis by 1,2-dimethylhydrazine dihydrochloride.

The effect of the antioxidant vitamin E on the tumor-inducing ability of 1,2-dimethylhydrazine dihydrochloride (1,2-DMH) was investigated in randomly bred Swiss mice. Three groups of mice that were 6 weeks of age at the beginning of the experiment received the following treatments: a) vitamin E acetate [DL-alpha-tocopheryl acetate (TA)] at a 4% dose level in a powdered diet for life; b) 1,2-DMH, 10 weekly sc injections at 20 micrograms/g body weight; c) combination of a and b treatments. The administration of TA enhanced the tumorigenicity of 1,2-DMH, as evidenced by statistically significant incidences of tumors in the duodenum, cecum, colon, rectum, and anus. The present finding apparently is in contrast with the reported inhibitory effect of TA on colon carcinogenesis by 1,2-DMH.

1,2-Dimethylhydrazine↗