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PubMed1990

[Ornithine decarboxylase activity and polyamine contents in 1,2-dimethylhydrazine-induced carcinogenesis of the intestines in rats].

The ornithine decarboxylase (ODC) activity and concentration of polyamines have been studied in small and large intestine during 1,2-dimethylhydrazine-induced carcinogenesis in rats. Changes in the polyamine biosynthesis consisting both in enhanced ODC activity and an increase of the intracellular content of putrescine, spermidine and spermine. Process of the polyamine synthesis activation proceeds in two phases: the most expressed and similar changes in polyamine metabolism factors have been observed at early (the 1st month) and late (the 5th-6th months) stages of carcinogenesis. It is supposed that intensification of the polyamine synthesis is a typical feature of malignization in the gastrointestinal tract.

1,2-Dimethylhydrazine↗
PubMed1990

[1,2-dimethylhydrazine induction of epithelial tumors of the kidneys in CBA strain mice].

The results of experiments on the 1,2-dimethylhydrazine (DMH) induction of epithelial renal tumours in CBA male mice are presented. The dose-response study shows a sharp increase (from 5 to 75%) of the epithelial renal tumour incidence in the range of 2, 4 and 8 injections of DMH. Higher doses induce a decrease of the tumour incidence due to the early death caused by other tumours. DMH is shown to be the most powerful renal carcinogen in mice. Serial sacrifice of mice after 5 injections of DMH is a convenient model for the study of renal carcinogenesis in mice. Main histological types of epithelial renal tumours are illustrated.

1,2-Dimethylhydrazine↗
PubMed1990

Chemoprevention of 1,2-dimethylhydrazine-induced colon cancer in mice by naturally occurring organosulfur compounds.

Organosulfur compounds (OSCs) present in garlic and onion oil have been shown to inhibit chemical carcinogenesis. In this study, we compared the chemopreventive efficacy of five lipid- and four water-soluble OSCs using the murine nuclear aberration assay. Administration of diallyl sulfide and S-allyl cysteine p.o. at a dose of 200 mg/kg 3 h prior to i.p. 1,2-dimethylhydrazine (DMH) injection (20 mg/kg) significantly inhibited colonic nuclear damage in female C57Bl/6J mice by 47% and 36%, respectively. The inhibitory effect of S-allyl cysteine was found to be dose dependent. The other OSCs did not affect the level of DMH-induced nuclear toxicity. Furthermore, the incidence and frequency of colonic tumors induced by DMH (20 mg/kg, 10 weekly i.p. injections) in female CF-1 mice were significantly inhibited by S-allyl cysteine pretreatment, given 3 h prior to each carcinogen injection. These data indicate that the allyl group coupled to a single sulfur atom might play an important structural role in inhibition of DMH-induced colonic nuclear toxicity and carcinogenesis. OSCs containing allyl groups stimulated glutathione S-transferase activity in both the liver and colon. However, their saturated analogues stimulated little or no hepatic and colonic glutathione S-transferase activity. Induction of hepatic and colonic glutathione S-transferase might assist in detoxification of carcinogens and could be necessary for some aspects of chemoprevention.

1,2-Dimethylhydrazine↗
PubMed1988

[Lectin histochemistry of 1,2-dimethylhydrazine-induced rat colonic neoplasia and human colorectal neoplasia].

In order to study changes in complex carbohydrates of the cellular membrane and cytoplasm in neoplasia of large intestine, lectin-binding patterns were histochemically determined in 1,2-dimethylhydrazine (DMH)-induced rat neoplasia and human specimens using peroxidase-labelled lectins (PNA, WGA, UEA-1) with different sugar-binding specificities. The results obtained were as follows: 1) There was a difference in lectin-binding patterns among sites within the large intestine in rats. 2) There were differences in the lectin-binding patterns of PNA, WGA and UEA-1 between neoplastic and non-neoplastic mucosae in both rat and human distal large intestine. This result was considered to reflect the changes involved in the metabolism of complex carbohydrates accompanying malignant change. The cancerous cell surface showed a higher degree of binding than that of non-neoplastic mucosa, and irregular binding patterns of each lectin were characteristically observed in the cytoplasm. 3) UEA-1 showed the highest level of binding for human carcinoma, followed by adenoma and non-neoplastic mucosa, in that order, suggesting recognition of tumor-associated complex carbohydrates. 4) In the cytoplasm of mucosa adjacent to carcinoma, rat PNA and UEA-1 and human PNA showed high degrees of binding, probably expressing biochemical changes in cellular function that have not been observed in conventional morphological studies.

1,2-Dimethylhydrazine↗
PubMed1989

Suppression of a a carcinogen (1,2-dimethylhydrazine dihydrochloride)-induced increase in mitotic activity in the colonic crypts of rats by addition of dietary cellulose.

Serial injections of the colon carcinogen, 1,2-dimethylhydrazine (DMH), have been reported to increase the proliferative activity in the colonic crypts preceding development of tumors. Can addition of purified cellulose to a fiber-free AIN-76 rat diet be used to suppress this increase in proliferative activity? To answer this question rats were divided into two groups, and one group was given eight weekly injections of the DMH base at 9.5 mg/kg of body weight. Throughout this period and for 2 additional wk the rats were isocalorically fed a defined nutritionally complete diet both with and without different dietary levels of cellulose (0, 5, and 15%). The rats were given injections of colchicine 3 h prior to sacrifice to arrest and to collect dividing cells at metaphase. Analysis of variance was performed on various morphometric parameters obtained from histological sections of midaxial crypts from the descending colon. Our results confirm that DMH induced a significant increase in the mitotic activity as measured by the number of metaphase figures per crypt. The presence of dietary cellulose did cause a significant suppression of the DMH-induced increase in the crypt mitotic activity.

1,2-Dimethylhydrazine↗
PubMed1989

Effect of dietary cellulose on cell proliferation and progression of 1,2-dimethylhydrazine-induced colon carcinogenesis in rats.

The effects of different levels of dietary cellulose on colonic crypt mitotic activity and colon carcinogenesis were studied in 190 male Sprague-Dawley rats. Rats were divided into groups and fed a basal fiber-free diet supplemented with either 0, 5, or 15% pure cellulose (w/w), for periods of 10 weeks (initiation stage) or 32 weeks (promotional stage). Half of the rats in each group were given weekly s.c. injections of 9.5 mg 1,2-dimethylhydrazine (the base) (DMH) for 8 weeks. Some of the rats were killed at 10 weeks while most were killed 22 weeks later. In some groups the dietary cellulose level was changed to a different level at 10 weeks. Food intake and body weight data showed that the rats within each experiment were isocalorically fed. There was a direct correlation between crypt height and the percentage of cellulose in the diet. Addition of 5 or 15% dietary cellulose during the initiation stage of carcinogenesis resulted in a significant increase in crypt height. Increasing dietary cellulose after the initiation stage (0 to 5% and 5 to 15%) or maintaining a high dietary cellulose level throughout both the initiation and promotional stages (15%) resulted in a significant increase in crypt height. A DMH-induced increase in mitotic activity that was observed during the initiation stage was no longer evident after the 22-week promotional stage. The significant DMH-induced increases in proliferative zone height and crypt height that were initially observed during the initiation stage were also observed after the 22-week promotional stage. These data indicate that the initial DMH-induced increases observed in proliferative zone height and crypt height are irreversible. Addition of 5 or 15% cellulose was found to suppress DMH-enhanced mitotic activity in the crypts of the descending colon during the initiation stage of carcinogenesis. This finding was correlated with a significantly lower incidence of adenocarcinomas in rats maintained on 5 or 15% cellulose throughout both the initiation and promotional stages.

1,2-Dimethylhydrazine↗
PubMed1989

[Induction of renal tumors in monkeys as a result of probable prenatal effects of 1,2-dimethylhydrazine].

Prenatal treatment with 1,2-dimethylhydrazine induced embryonal nephroma in two out of six monkeys. In one case, tumor of the right kidney disseminated to the lower lobes of both lungs. Induced embryonal nephroma of monkey proved similar to Wilms' tumor, a frequent pediatric pathology, in terms of histologic pattern, duration of latent period and clinical course.

1,2-Dimethylhydrazine↗
PubMed1989

[Endoscopic study on the effect of dietary fiber against 1,2-dimethylhydrazine-induced colonic carcinogenesis in rats].

The effect of dietary fiber on colonic carcinogenesis was studied endoscopically in rats administered 1,2-dimethylhydrazine. Colonic tumors appeared about six weeks later in rats fed 15% cellulose diet or 40% wheat bran diet than in those fed basal diet. Furthermore, the incidence of colonic tumor was significantly lower from 23th week to 26th week in the cellulose diet group (p less than 0.01) and at 26th week in the wheat bran diet group (p less than 0.05) than in the basal diet group. However, the incidence of colonic tumors and the mean number of tumors per rat at sacrifice (30th week) were not significantly different between these two high-fiber diet groups and the basal diet group. These two diets significantly increased feces 3 to 4 times in weight and 5 times in volume over the base diet. However, 15% pectin diet could neither inhibit colonic carcinogenesis nor increase the fecal weight. These results suggested that cellulose and some dietary fibers of wheat bran were effective to retard colonic carcinogenesis, and that the increased fecal weight and volume by fibers may be involved in the inhibitory effect.

1,2-Dimethylhydrazine↗
PubMedDate not supplied

Sulfasalazine alters the character of dimethylhydrazine-induced colorectal carcinoma in rats.

The etiologic variables involved in the increased incidence of colorectal carcinoma in patients with chronic ulcerative colitis have not been defined. Sulfasalazine is the most commonly used medication in the treatment of ulcerative colitis. It is not known whether the pharmacologic treatment of ulcerative colitis alters the incidence of cancer in man, but a drug related to sulfasalazine has been shown to reduce the incidence of colorectal carcinoma in rats. In this study we examined the effect of sulfasalazine on the development of 1,2-dimethylhydrazine-induced (DMH) colorectal carcinogenesis in rats. Daily oral ingestion of sulfasalazine in doses equivalent to human daily doses resulted in serum salicylate levels in those animals that were comparable to human therapeutic serum salicylate levels. Sulfasalazine administration did not significantly effect the incidence of DMH-induced colorectal tumors. However, sulfasalazine treated animals were found to have significantly smaller tumors and to show a trend towards multiple, flat, sessile, frequently microinvasive tumors compared to the fewer, larger, exophytic tumors observed in animals treated only with DMH. These results demonstrate that in the doses given, sulfasalazine treatment alters the character of DMH-induced colorectal tumors without significantly effecting tumor incidence.

1,2-Dimethylhydrazine↗
PubMed1989

Tumor induction in mice administered neonatally with 1,2-dimethylhydrazine.

1,2-Dimethylhydrazine was given subcutaneously to neonatal ICR mice, and animals were observed for one year. The tumors of lung and liver, malignant lymphoma, and other tumors were induced. In the mice given DMH 30 mg/kg of body weight, two mice developed colonic tumor, and the incidence of colonic tumor was low.

1,2-Dimethylhydrazine↗
PubMed1989

Urinary excretion of N1-acetylspermidine and other acetylated and free polyamines in the 1,2-dimethylhydrazine model of experimental rat colon cancer.

1,2-Dimethylhydrazine (DMH) is a potent procarcinogen with selectivity for the colon. Recently, it has been demonstrated that levels of N1-acetylspermidine were elevated 2-3-fold in colonic tumors induced by this agent compared to control tissues. To determine whether alterations in the urinary levels of this acetylated polyamine or other polyamines were useful biochemical markers for colon cancer in this experimental model, rats were given s.c. injections of DMH (20 mg/kg body weight/week) or diluent for 26 weeks. One week after the last injection, control and DMH-treated animals were placed in separate metabolic cages and their urine was collected for 24 h. The urinary levels (expressed as nmol/mg creatinine) of putrescine, spermidine, spermine, N1-acetylspermidine, and N8-acetylspermidine were then analyzed by high-performance liquid chromatography. Animals from each group were then sacrificed and their colons were examined for tumors. The results of these studies demonstrated that the urinary level of N1-acetylspermidine was an excellent biochemical marker for colonic tumors induced by DMH. At 18.3 nmol/mg creatinine, N1-acetylspermidine was 100% sensitive and specific for colon cancer. Moreover, urinary levels of N1-acetylspermidine were better for this purpose than the N1-acetylspermidine/N8-acetylspermidine molar ratio, a marker previously suggested to be more specific for certain cancers than free polyamines.

1,2-Dimethylhydrazine↗
PubMed1989

Chloroform inhibition of 1,2-dimethylhydrazine-induced gastrointestinal tract tumors in the Fisher 344 rat.

The effect of chloroform (CHCl3), administered at 0, 900, and 1800 mg/liter in the drinking water, on the carcinogenic potency of 1,2-dimethylhydrazine (DMH) was investigated. Groups of 40 male Fisher 344 rats were given one of the three drinking water solutions for 39 weeks following the subcutaneous injection of 200 mg/kg DMH, a known gastrointestinal (GI) tract carcinogen in this animal strain. When tumors from the GI tract were pooled there was a highly significant (p less than 0.001) decrease in total number of tumors per group with increasing concentration of drinking water CHCl3. In the control group (0 mg/liter CHCl3), 14/39 (36%) of the animals developed tumors of the GI tract, including the duodenum, jejunum, stomach, cecum, and colon. In contrast, the incidence of tumors in the two groups of rats given CHCl3 in the drinking water was significantly lower (p less than 0.001; 900 mg/liter CHCl3, 12.8%; 1800 mg/liter CHCl3, 12.5%). A similar relationship was obtained when colon tumors were analyzed independently (p = 0.01). The incidence of total colon tumors obtained in the control group of this study (10/39, 26%) agrees well with the previous study by B.S. Reddy, K. Watanabe, and J.H. Weisburger (1977, Cancer Res. 37, 4156-4159) conducted in the same rat strain (7/30, 23%). These results demonstrate that CHCl3 in the drinking water inhibits carcinogenesis in the rat GI tract.

1,2-Dimethylhydrazine↗
PubMed1989

[The production of epidermal growth factor and polypeptides similar to it in the intestinal mucosa of rats in 1,2-dimethylhydrazine-induced carcinogenesis and compensatory regeneration].

The production of EGF and EGF-like polypeptides in the normal intestinal mucosa and during 1,2-dimethylhydrazine (DMH)-induced carcinogenesis and postresection regeneration was studied in albino rats using chromatographic separation of acid-ethanol extracts. Fractions after gel filtration on Biogel P-60 with subsequent reverse-phase high performance liquid chromatography in acetonitrile gradient were tested in radioreceptor assay for competition with EGF. It has been established that intestinal tumours induced by DMH and regenerating intestinal mucosa have amplified production of EGF--alpha-TGF and related proteins of high molecular weight (approx. 30; 45-55; 120 kD) with the EGF-competitive activity. It is supposed that the high molecular weight EGF-competitive material represents nonprocessed forms of EGF and/or alpha-TGF which are accumulated in rapidly proliferating low-differentiated cells due to the intensified expression of their genes.

1,2-Dimethylhydrazine↗
PubMed1989

Apoptosis (cell death) induced in mouse bowel by 1,2-dimethylhydrazine, methylazoxymethanol acetate, and gamma-rays.

Apoptosis is a pattern of cell death involving nuclear pyknosis, cytoplasmic condensation, and karyorrhexis. The frequency of apoptosis after treatment with two colon carcinogens and radiation was studied in the crypts of five different portions of mouse bowel. When 1,2-dimethylhydrazine (DMH) was injected s.c., the earliest rise in apoptotic incidence after a high dose (200 mg/kg) was noted at 3 h in small intestine and at 6 h in large bowel. After i.p. administration of methylazoxymethanol (MAM) acetate, apoptotic cells were seen in large bowel after 3 h. When the plateau values attained after high doses of DMH were compared, many apoptotic cells were found in the lower part of the large bowel, whereas few such cells were observed in the small intestine and the upper part of the large bowel. This finding was reversed in the case of radiation-induced apoptosis. In the descending colon, a definite circadian rhythm in the apoptotic incidence was observed 6 h after injection of DMH or MAM acetate. Apoptosis showed a high incidence when these drugs were given between 2400 h and 0900 h, but a low incidence after administration between 1200 h and 2100 h. In the small intestine a rhythm was also noted for MAM acetate, but not significantly for DMH.

1,2-Dimethylhydrazine↗
PubMedDate not supplied

Inhibition of 1,2-dimethylhydrazine-induced nuclear damage in rat colonic epithelium by chlorophyllin.

Chlorophyllin (CHL) was tested for its effect on 1,2-dimethylhydrazine (DMH)-induced nuclear aberrations in rat colonic epithelium. Rats were given water containing CHL (1.5 mM) and food ad libitum. After 5 wks on this dietary regimen, the rats were given a single intraperitoneal injection of DMH (20 mg DMH base/kg body weight). The rats were sacrificed 18 hours later and their colons were removed. Ten consecutive crypts from the proximal and distal portion of each specimen were scored for nuclear aberrations and the karyorrhectic index (KI) was determined. Rats receiving CHL + DMH had significantly fewer nuclear aberrations (lower KI) in the colonic epithelium than rats given DMH alone. This implies that CHL, a known antimutagen, may have anticarcinogenic properties as well.

1,2-Dimethylhydrazine↗
PubMed1988

Hepatocyte initiation during continuous administration of diethylnitrosamine and 1,2-sym-dimethylhydrazine.

Hepatocyte initiation, as indexed by growth-selected gamma-glutamyl transferase-positive foci, was measured during continuous exposure to diethylnitrosamine (DEN) at concentrations used in previous DEN bioassay, DNA adduct, and cell replication studies. Hepatocyte initiation increased in a dose- and lobe-specific manner. The efficiency of DEN as an initiating agent was not affected by DEN dose rate over concentrations ranging from 4 to 40 ppm. In a similar experiment the initiating abilities of 1,2-sym-dimethylhydrazine and DEN were compared under continuous exposure regimens. Foci induction increased in a lobe- and time-dependent manner. When left and median lobes were compared, the initiating ability of the two compounds correlated with their carcinogenicity. However, when corresponding anterior lobes were compared, no such correlation was observed.

1,2-Dimethylhydrazine↗