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PubMed1996

Inhibitory effect of dietary wheat bran on formation of aberrant crypt foci in rat colon induced by a single injection of 1,2-dimethylhydrazine.

The frequency of appearance of aberrant crypt foci (ACF) in the distal colon was significantly lower in rats fed a high fiber (20% wheat bran) diet than in those fed a fiber-free one at 4 weeks after a single injection of 1,2-dimethylhydrazine (DMH, 20 mg/kg), although crypt/ACF was high in the former relative to the latter. This result suggests that dietary wheat bran effectively serves as a regulator of ACF frequency at early stages after DMH injection.

1,2-Dimethylhydrazine↗
PubMed1981

The response of three inbred strains of rat to the carcinogen 1,2-dimethylhydrazine.

Rats of 3 inbred strains (DA, HS and AS2) were dosed with 1,2-dimethylhydrazine 2HCl (DMH) or saline by gavage weekly for 10 wk. DA and HS rats showed little overt toxic reaction but all AS2 rats died following DMH doses of 30 mg/kg. However, at 10 mg/kg 60% of AS2 rats survived the 30 wk experiment. All DA rats developed a high yield of adenocarcinoma of the bowel (means: males 6.8 tumours/large bowel and 0.8/small bowel; females 2.8/large and 0.08/small bowel) and one-third of the males developed tumours of the ear canal. A smaller proportion (52%) of HS rats developed tumours, specifically bowel tumours (means: male 1.4/large and 0.2/small bowel; females 0.4/large and 0.1/small bowel). Even on the lower dose of DMH AS2 rats showed extensive liver changes including cystic cholangioma (58%), angiosarcoma (25%) and hepatocellular carcinoma (8%) and 83% developed bowel tumours (means: males 2.3/large and 1.5/small bowel; females 3.5/large and 1.0/small bowel). The rapid induction and high yield of bowel tumours, the different toxicity of DMH in AS2 rats, and the differences in relative tumour density both between sexes and in the various segments of the bowel indicate the potential of these strains for studies of carcinogenesis in the bowel.

1,2-Dimethylhydrazine↗
PubMed1981

Adenosine and guanosine 3',5' cyclic monophosphate phosphodiesterase activities in rat small and large bowel following single and multiple exposure to 1,2-dimethylhydrazine.

The hydrolytic activities of adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterases (PDE) in rat large and small bowel tissue were determined after exposure to the colon carcinogen 1,2-dimethylhydrazine (DMH). Immediate increases in the cAMP-PDE activities were found in the tissues after a single exposure to the chemical which returned towards normal while chronic exposure resulted in no visible changes. The increased cAMP-PDE activities may be the factor responsible for the diminished intracellular cAMP concentrations found after exposure to the carcinogen. In contrast, the cGMP-PDE activities changed little in the colon and increased in the small bowel, suggesting that the determinant for the increases in the concentration cGMP was the activation of guanylate cyclase enzymes following exposure to DMH. Ratios of cAMP to cGMP and cAMP-PDE to cGMP-PDE in the colon showed major changes after carcinogenic insult by the DMH, suggesting that such measurements might serve as useful markers for exposure to environmental toxicants.

1,2-Dimethylhydrazine↗
PubMed1986

Enhancing effect of carrageenan on the induction of rat colonic tumors by 1,2-dimethylhydrazine and its relation to beta-glucuronidase activities in feces and other tissues.

Since it has been demonstrated that a high level of fat is a dietary factor in the etiology of colon cancer, the effect of carrageenan, a polysaccharide extracted from the red seaweeds, on 1,2-dimethylhydrazine-induced colonic tumors in rats fed a semipurified control diet containing an ordinary level of fat was studied. Nevertheless, the enhancing effect of carrageenan on colonic tumors was observed. The rats fed a carrageenan diet had approximately twice the fecal weight compared to the rats fed a control diet. While no significant differences were found in beta-glucuronidase activities in colonic mucosa, liver or plasma in the carrageenan-fed rats and controls, the activity in feces was significantly lower in the carrageenan-fed rats. At least, no beta-glucuronidase activity seemed to be related to the tumor-enhancing effect of carrageenan.

1,2-Dimethylhydrazine↗
PubMed1994

Food deprivation increases apoptotic cell counts induced by 1,2-dimethylhydrazine in rat descending colonic and rectal crypts.

The frequency of apoptosis after treatment with 1,2-dimethylhydrazine (DMH) was counted in the descending colonic and rectal crypts of food-deprived and fed rats. Food-deprived or fed rats were subcutaneously injected with DMH (100 mg/kg body weight). Six hours after the injection, apoptotic cells were observed in crypt regions by light microscopy. The incidence of DMH-induced apoptosis in food-deprived rats was significantly higher than in fed rats. The incidence appeared to be higher in descending colon than in rectum. PAS staining revealed that DMH treatment lowered mucin secretion in crypts, which was substantially lowered by food deprivation. The effect of food deprivation on apoptosis induced by DMH may be due to the decrease in mucus barrier against DMH.

1,2-Dimethylhydrazine↗
PubMed1996

Administration of anti-asialo GM1 serum increases aberrant crypt foci induced by 1,2-dimethylhydrazine in the large bowel of rats.

We investigated the influence of the administration of anti-asialo GM1 antibody on aberrant crypt foci (ACF) formation induced by a single injection of 1,2-dimethylhydrazine (DMH). At four weeks after the injection of DMH (20 mg/kg body weight), the number of ACF and aberrant crypts were counted. Most ACF appeared in the distal large bowel, accounting for approximately 60% of the total ACF in both groups. Rats administered anti-asialo GM1 had significantly more ACF in the distal colon, the rectum and the total large bowel as compared to control rats. A similar tendency was observed for the number of aberrant crypts. The increased number of ACF resulting from the administration of anti-asialo GM1 was not accompanied by the enlargement of ACF size in every part of the colon. This study demonstrated that the administration of anti-asialo GM1 at the initiation stage leads to an increase in ACF as well as aberrant crypts in the distal colon, rectum and total large bowel probably via the suppression of natural killer cells.

1,2-Dimethylhydrazine↗
PubMed1992

Action of hydrazine drugs in tumor-free and 1,2-dimethylhydrazine-treated male rats.

In order to evaluate possible carcinogenesis, young adult male Sprague-Dawley rats were fed diets of hydralazine, phenelzine, and isoniazid at levels of 0.020-0.035% for 87 weeks. Hydralazine and isoniazid were also tested by the subcutaneous (sc) route at weekly dosages of 17 and 83 mg/kg, respectively, in both intact and partially hepatectomized rats, but many succumbed after 7 to 49 weeks of treatment. Gastrointestinal lesions were absent and, of the miscellaneous changes, sc lesions occurred sporadically among the control and drug-treated groups. As a further criterion, male weanlings were placed on the diets and, starting on day 15, 1,2-dimethylhydrazine (DMH) was injected sc at 9.0 mg/kg once weekly for the first 7 weeks and twice per week for a total of 23 treatments. The rats were killed 22 weeks after the last injection, at which time colon adenocarcinomas were observed in over 80% per group, the total number being significantly greater for the isoniazid group due to heightened tumor occurrence at the distal colon. The tumor number in the descending colon for phenelzine was also increased but the overall score, as with the hydralazine group, was in the range of the DMH injected controls. Small intestinal adenocarcinomas were lower in number and involved fewer rats on the hydralazine and phenelzine diets as compared to the isoniazid and control groups. Based on the current data, it is concluded that on long term exposure of DMH treated rats to the monoamine oxidase inhibitors, hydralazine and phenelzine are not cocarcinogenic, whereas isoniazid enhances colon carcinogenicity.(ABSTRACT TRUNCATED AT 250 WORDS)

1,2-Dimethylhydrazine↗
PubMedDate not supplied

Chlorophyllin, an antimutagen, acts as a tumor promoter in the rat-dimethylhydrazine colon carcinogenesis model.

Chlorophyllin (CHL), the water soluble sodium/copper salt of chlorophyll, was investigated for its effect on colorectal cancer risk in the rat-dimethyldrazine colon carcinogenesis model. Ninety weanling Fisher 344 male rats were treated with five weekly injections of 1,2 dimethylhydrazine (DMH), 20 mg base/kg body weight. Rats had been previously divided into three groups, consuming either rat chow and water (Group I), rat chow and CHL 1.5 mM in water throughout the experiment (Group II), or water and rat chow during DMH injection, adding CHL 1.5 mM to the drinking water after completion of the DMH treatments. At sarcifice, the incidence and yield of colorectal tumors were as follows: Group I 10% and 0.1; Group II, 23% and 0.27; and Group III, 47% and 0.53 (p less than 0.005 for incidence and = 0.003 for yield). These data demonstrate that, though it is well established that CHL is an antimutagen, CHL in this colorectal carcinogenesis model acted as a tumor promoter.

1,2-Dimethylhydrazine↗
PubMedDate not supplied

Effect of metabolic inhibitors, methylxanthines, antioxidants, alkali metals, and corn oil on 1,2-dimethylhydrazine carcinogenicity in rats.

The effect of the oral administration of 10 compounds on 1,2-dimethylhydrazine (DMH) carcinogenesis was investigated in 180 male Wistar rats and 510 male BD6 rats. DMH, administered s.c. once per week for 20 consecutive weeks (20 mg/kg body wt/dose), produced intestinal (mainly colon) tumors of various histological type in 100% of both rat strains and, in addition, caused Zymbal gland carcinomas in 79.7% of Wistar rats. Pretreatment with disulfiram (DSF, 500 mg/kg), a known inhibitor of DMH metabolism, totally prevented intestinal and Zymbal gland tumors in Wistar rats. When DSF treatment started after the first DMH injection, the protective effect was not total, the incidence and multiplicity of both types of tumors being comparable to those observed following a single injection of the carcinogen alone. This confirms the involvement of DSF in the initiation stage only of DMH carcinogenesis. A complete prevention of intestinal tumors in BD6 rats was also produced not only by the DSF metabolite carbon disulfide (250 mg/kg) but also by the hepatotoxic agent carbon tetrachloride (1.5 ml/kg), which suggests that the block of DMH metabolism in rat liver is not an exclusive property of thiono-sulfur compounds. Butylated hydroxytoluene (BHT) decreased the multiplicity of intestinal tumors, but not to a significant extent. BHT and the aforementioned metabolic inhibitors were administered by gavage in corn oil, which per se did not significantly decrease intestinal or Zymbal gland tumors. All remaining modulators were administered with drinking water. Two additional antioxidants triggered opposite effects on the multiplicity of intestinal tumors. In fact, sodium selenite (10 mg/l) significantly decreased the number of tumors, whereas ascorbic acid (10 g/l), irrespective of its combination with CaCl2, produced a marked enhancement. The alkali metal salts CaCl2 and KCl (both at 5 g/l) as well as the methylxanthines caffeine and theophylline (both at 600 mg/l) were devoid of significant effects. Neither treatment with DMH alone nor its association with test modulators was accompanied by significant changes in body weight gain or survival of animals. On the whole, depending on the mechanisms involved, the comparative study of test compounds led to a broad array of effects on DMH carcinogenesis, ranging from complete inhibition to significant enhancement. The resulting picture can be visualized at a glance in Figure 1 of this article.

1,2-Dimethylhydrazine↗
PubMed2006

Distribution of preneoplastic lesions and tumors, and beta-catenin gene mutations in colon carcinomas induced by 1,2-dimethylhydrazine plus dextran sulfate sodium.

Mucin-depleted foci (MDF) are considered as useful biomarkers in rat colon carcinogenesis. The purpose of the present study was to examine the mechanism(s) underlying rat colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH) plus 1% Dextran Sulfate Sodium (DSS). Twelve male F344 rats were given subcutaneous injections (40mg/kg body) of DMH twice a week. They received DSS in the drinking water for 1 week after the first injection of DMH and then were maintained on tap water. The rats were sacrificed at 10 and 14 weeks after the first injection of DMH. Colon tissues were divided into 10 segments from anus to cecum (A/J) and stained with Alcian blue (AB) to identify MDF. We found that MDF and tumors were induced in the rat colon after treatment with DMH plus DSS and that the number of MDF in each segment of the colon was significantly correlated with that of tumors (p=0.006). In addition, we found that the beta-catenin protein was accumulated in cytoplasm and nuclei of MDF and the frequent beta-catenin gene mutations in the colon tumors. These results suggest that MDF is closely related to rat colon carcinogenesis induced by DMH plus DSS.

1,2-Dimethylhydrazine↗
PubMedDate not supplied

[The incidence of 1,2-dimethylhydrazine-induced colonic neoplasms in the rat: the effect of constipation].

The authors studied the role of slow bowel transit in the development of colonic neoplasias in rats treated with 1,2-dimethylhydrazine (DMH). Forty Sprague-Dawley male rats, weighing 400 g, were used in the experiment and were divided into 4 groups of 10 rats each. The first and the second group were given, weekly, subcutaneous injections of DMH at a dose of 25 mg/kg for 25 and 27 weeks respectively; in these groups constipation was obtained by reducing water intake throughout the period of the experiment. The third and the fourth group (control groups) received DMH at the dose of 25 mg/kg for 25 and 27 weeks respectively and water "ad libitum". The rats were weighed once a week and stool output, weight, and number of scybala/day were recorded once every four weeks. Rats were sacrificed one week after the final injection of DMH and every intestinal lesion macroscopically identified was histologically examined. All rats showed weight loss from the 22nd week to the sacrifice. The mean stool weight/day was 21.2 g +/- 1.47 in the groups A and B; while for the groups C and D it was 23.6 g +/- 1.81 (p = 0.019). The number of scybala/day was 26 +/- 3 in the groups A and B, whereas in the groups C and D was 34 +/- 4 (p = 0.05). An increased number of cancers per rat was recorded in the groups A and B compared to control groups, respectively from 0.66 to 1.4 at 25 weeks (p = 0.02) and from 0.9 to 2.44 at 27 weeks (p = 0.07). A corresponding increase in the number of polyps after 25 weeks was demonstrated, taking into account the possible polyp-cancer sequence. Our study suggests that the slow bowel transit induced an increased number of colonic neoplasia in relation to the prolonged contact of the carcinogen with the mucosa or to its greater concentration in the colonic lumen due to the fecal output reduction.

1,2-Dimethylhydrazine↗
PubMed1991

Dietary calcium and vitamin D modulate 1,2-dimethylhydrazine-induced colonic carcinogenesis in the rat.

To determine whether supplemental dietary calcium and/or vitamin D deficiency are involved in modulating colon cancer induced by 1,2-dimethylhydrazine (DMH), Sprague-Dawley rats were fed diets containing either: (a) a normal content of calcium (0.87%) and phosphorus (0.60%) with 2.2 IU of vitamin D3 per g of feed (group A); (b) the same diet as group A, but with calcium and phosphorus increased to 1.80 and 0.80%, respectively (group B); or (c) a vitamin D-deficient diet with supplemental calcium (1.80%) and phosphorus (0.80%) (group C). After 6 weeks on their respective diets, one-half the animals in each group were given s.c. injections of either vehicle or DMH (20 mg/kg body weight/week) for 26 weeks. Animals were then sacrificed and the incidence of tumors as well as the number of tumors per tumor-bearing rat were determined. Colonic mucosal polyamine levels were measured after 15 weeks of exposure to vehicle or DMH, before development of histologically recognizable neoplasms. The results of these experiments demonstrated that neither calcium supplementation alone nor supplemental calcium in conjunction with vitamin D deficiency altered the incidence of colonic cancer induced by this carcinogen. Supplemental calcium, however, significantly decreased the number of rats with multiple tumors and reduced tumor size. Moreover, vitamin D deficiency abolished these protective effects of calcium on colon cancer in this experimental model. DMH treatment increased polyamine levels in the premalignant colonic mucosa in group A rats. This carcinogen-induced effect was blunted by high dietary calcium. Vitamin D-deficient, calcium-supplemented rats (group C) showed an increase in N1-acetylspermidine, but not the other polyamines, with DMH treatment.

1,2-Dimethylhydrazine↗
PubMed1990

[Primary localization of 1,2-dimethylhydrazine-induced cancer in lymphoid patches of the large intestine].

Treatment with 1,2-dimethylhydrazine was performed according to body surface. The occurrence of tumors in the area of lymphoid patches in the ascending and descending parts of the colon was 6.7 and 1.5 times that outside the site, respectively. Signet-ring cell and mucinous carcinomas made up 92% of tumors arising in lymphoid patches. Treatment with the carcinogen was associated with decrease in the labelling index in lymphoid elements of interfollicular (T-dependent) zones of lymphoid patches from 6.6 +/- 1.8 to 4.1 +/- 1.6%.

1,2-Dimethylhydrazine↗
PubMedDate not supplied

Effects of dietary fish oil and corn oil on protein kinase C distribution in the rat colon with and without 1,2 dimethylhydrazine treatment and in rat colonic adenocarcinoma.

The activity and subcellular distribution of Protein Kinase C (PKC) was determined in the colons of Sprague-Dawley rats that were fed either a low fat rat chow or rat chow supplemented with 17% corn oil (40% ingested calories as fat). Rats given the high fat diets were either given no carcinogen or treated prior to or subsequent to the initiation of the test diets with 1,2 dimethylhydrazine (DMH). Rats were sacrificed and PKC activity determined in the soluble and particulate fractions of the colonic tissue 13 weeks after the initiation of the diets or DMH treatment, which was before tumor induction. In addition several rats were maintained on their diets until colon tumor formation occurred and PKC activity determined in the colonic tumor and compared to age matched control colonic tissue. In the absence of DMH, fish oil and corn oil equally augmented PKC activity and decreased the ratio of soluble/particulate PKC. With DMH treatment, corn oil augmented PKC as above, but fish oil supplementation resulted in a pattern of PKC activity and distribution more typical of a low fat diet, particularly when fish oil supplementation preceded DMH treatment. PKC activity in DMH induced colonic carcinomas was markedly depressed regardless of the fat source in the diet, when compared to colonic tissue from a non-DMH treated age matched low fat control.

1,2-Dimethylhydrazine↗
PubMed1991

Effect of dietary carbohydrates on the growth of dysplastic crypt foci in the colon of rats treated with 1,2-dimethylhydrazine.

The effect of dietary starch and sucrose on the growth of foci of dysplastic crypts in the colon (FDC) was studied in female Sprague Dawley rats treated twice p.o. with 25 mg/kg of 1,2-dimethylhydrazine (DMH). After DMH administration, the animals were fed high-fat (23% corn oil, w/w)/low-calcium (0.1%, w/w)/low-cellulose (2%, w/w) diets in which carbohydrates were represented by corn starch (starch diet) or sucrose (sucrose diet) (46%, w/w). The animals were fed for either 30 or 105 days with the experimental diets. The number of FDC was not significantly affected by diet. However, after 30 days the percentage of small FDC (formed by 1-2 dysplastic crypts) was higher in the animals fed the starch diet compared to the animals fed the sucrose diet [90.3 +/- 1.1% (SE) and 82.6 +/- 3.1%, respectively; P less than 0.05]. In contrast, foci formed by 3-4 dysplastic crypts were decreased by the starch diet (P less than 0.05). After 105 days of feeding, the starch diet induced a number of dysplastic crypts/focus lower than that induced by the sucrose diet (2.6 +/- 0.1 and 2.9 +/- 0.1, respectively; P less than 0.05). The percentage of small FDC was also higher in the animals fed the starch diet compared to animals fed the sucrose diet (P less than 0.01). After 30 days of feeding, DMH treatment increased colon proliferative activity in both dietary groups (P less than 0.05). But after 105 days of feeding, proliferation was similar in controls and DMH-treated rats and markedly reduced in animals fed the starch diet (mean labeling index values for both controls and DMH-treated rats were 10.4 +/- 0.8 and 4.4 +/- 0.5 in the sucrose and starch diets, respectively; P less than 0.001). The overall results suggest that starch in high-fat/low-calcium/low-cellulose diets has a protective role against DMH-colon carcinogensis in the rat.

1,2-Dimethylhydrazine↗
PubMed1990

[Effects of hyperthermochemotherapy on activities of DNA-synthesizing enzymes in 1, 2-dimethylhydrazine (DMH)-induced colon carcinomas in rats].

It has been known that a high incidence of adenocarcinoma in distal colon can be induced by s.c. injection of 1, 2-dimethylhydrazine (DMH) into rats at weekly intervals. We investigated effects of radiofrequency hyperthermia (RF-HT) in combination with anti-cancer drug UFT (a combination of tegafur and uracil) on activities of DNA-synthesizing enzymes, using colon carcinomas induced by DMH treatment in rats. 1) Thymidylate synthetase (TS), DNA-synthesizing enzyme in de novo pathway of pyrimidine metabolism, increased to approximately 7-fold that of normal control colon in DMH-induced colon carcinomas in activity, but was markedly reduced to 48% of that in the carcinomas by administration of UFT. 2) Thymidine kinase (TK) in salvage pathway increased to approximately 8-fold that of the control in the carcinomas in activity, but was markedly reduced to 25% of that in the carcinomas by RF-HT treatment. 3) The TK-isozyme, that was thought to be a fetal type in the intracellularly cytoplasmic fraction and closely involved in rapid DNA replication, increased to approximately 24-fold that of the control in the carcinomas in activity, but was reduced to the nearly same level as that of the control by RF-HT treatment. This isozyme was labile in thermostability and easy to be inactivated in low pH. 4) The activities of TS and TK in the carcinomas were extremely suppressed by UFT administration in combination with RF-HT treatment. These results indicate that hyperthermochemotherapy with UFT may serve as an available treatment for colon carcinomas.

1,2-Dimethylhydrazine↗
PubMed1990

1,2-Dimethylhydrazine-induced alterations in protein kinase C activity in the rat preneoplastic colon.

Recently, a number of studies in experimental animals and humans have suggested that alterations in the activity of protein kinase C (PKC) may be involved in the malignant transformation process. To determine whether such alterations in this kinase were present before the development of 1,2-dimethylhydrazine (DMH)-induced colon cancers, rats were given s.c. injections of this procarcinogen (20 mg/kg body weight/week) or diluent for 10 or 15 weeks. Animals were sacrificed after these time periods and colonic epithelium was harvested from each group. The activity and distribution of PKC in the cytosolic and membrane fractions of these preparations as well as 1,2-diacylglycerol mass and phosphoinositide turnover were then examined and compared in the presence and absence of 10 nM 1,25-dihydroxycholecalciferol, an agent which has previously been found to influence these biochemical parameters in the normal rat colonic epithelium. The results of these studies demonstrate that: (a) the percentage of PKC activity in the membrane fraction was significantly greater in DMH-treated animals compared to their control counterparts at 10 and 15 weeks; (b) the total PKC activity was similar at 10 weeks, but markedly reduced in the colonic mucosa of the DMH-treated group at 15 weeks; (c) 1,2-diacylglycerol mass and phosphoinositide turnover were increased in the colonic mucosa of rats administered this carcinogen at both time points; and (d) in control, but not in DMH-treated animals, in vitro addition of 1,25-dihydroxycholecalciferol increased PKC activity, 1,2-diacylglycerol mass and phosphoinositide turnover at each of the times studied. Based on these findings, it would appear that alterations in PKC activity may play a role in the malignant transformation process of the colon in animals administered DMH.

1,2-Dimethylhydrazine↗
PubMed1990

[Modifying effects of changes connected with pregnancy on 1,2-dimethylhydrazine-induced carcinogenesis in rats].

The modifying effect of pregnancy and lactation on carcinogenesis induced by single injection of 1,2-dimethylhydrazine to female rats 30 days before mating has been studied. The total incidence of malignant tumours in rats with pseudopregnancy, single pregnancy, pregnancy and lactation, repeated pregnancies was lower in comparison with virgin animals (75, 44, 68, 59 and 93%, respectively). Colon adenocarcinoma incidence in rats with single pregnancy or repeated pregnancies was lower than that in virgin rats (42, 49 and 76%, respectively). Protective effect was observed mainly in descending colon. The mesenchymal kidney tumours were not developed at all in rats with single pregnancy. In virgin animals it was 31%. The inhibition of tumour incidence in the liver (cholangioma, cholangiocellular carcinoma) was observed in rats with single pregnancy or pregnancy and lactation in comparison with virgin control (3, 5 and 24%, respectively).

1,2-Dimethylhydrazine↗