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PubMed1983

Early histopathologic events to evolution of colon cancer in C57BL/6 and CF1 mice treated with 1,2-dimethylhydrazine.

After administration of the intestinal carcinogen 1,2-dimethylhydrazine (DMH), C57BL/6J and CF1 mice were observed for early precursor lesions to large bowel cancer. Among the initial events seen following DMH treatment, an abrupt reduction in colonic DNA synthesis was the earliest lesion detectable. The frequency of aberrant colonic nuclei rose shortly after DMH treatment, reaching a maximum value 24 hours later and remaining elevated for 3 days following the exposure. Mucin changes, detected histochemically, and cell kinetic alterations in crypt proliferation rates were observed much later and were a constant feature for both strains following 4 weekly treatments with DMH, while carcinomas appeared in all animals 32 weeks after the start of DMH treatment. The quantitative comparison of these histopathologic observations for the early detection of colon cancer suggests that the induction of colonic nuclear aberrations in the mucosa of the large bowel might provide a sensitive and rapid indication of genotoxicity to this organ and thus might provide the basis for a screening methodology for colon carcinogens.

1,2-Dimethylhydrazine↗
PubMed1983

BALB/c mice fed milk or beef protein: differences in response to 1,2-dimethylhydrazine carcinogenesis.

The development of 1,2-dimethylhydrazine (DMH)-induced colon tumors and immune responses were investigated in male BALB/c mice fed six different equicaloric diets. Milk or beef at a low (11%) or high (33%) level supplied the dietary protein, and corn oil (primarily) at a low (5%) or high (30%) level supplied the fat. Eleven weekly injections of DMH (at 20 mg/kg mouse) or saline were administered. At 59 weeks of age, the milk-fed mice had a significantly higher (P less than or equal to .05) colon tumor incidence than the beef-fed mice, 67 and 16%, respectively. Tumor volume and colon weight in the milk-fed mice were also significantly greater. Low natural killer cell activity against [125I]5-iodo-2'-deoxyuridine-labeled colon tumor cells and high serum blocking of antitumor cell activity were observed in the milk-fed-mice. These mice also exhibited higher T-lymphocyte cytotoxicity against colon tumor cells. These results differ from those of our previous studies and those of numerous epidemiologic investigations.

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PubMed1983

Comparative study of the morphologic, histochemical, and proliferative changes induced in the large intestine of ICR/Ha and C57BL/Ha mice by 1,2-dimethylhydrazine.

The mouse model of 1,2-dimethylhydrazine (DMH)-induced colorectal carcinogenesis was studied to determine the susceptibility of different anatomic segments of the large intestine in ICR/Ha (susceptible) and C57BL/Ha (resistant) mice. In ICR/Ha mice numerous exophytic macroscopic neoplasms were found in the distal colon and rectum after 15 weekly injections of DMH (20 mg/kg). The proximal colon was free of any microscopic or macroscopic neoplasms. In contrast, C57BL/Ha mice given the same treatment showed no macroscopic neoplasms. However, foci of dysplastic crypts were observed throughout the large intestine of C57BL/Ha mice with highest incidence in the distal colon and rectum. In some areas dysplastic crypts were clearly invading the muscularis mucosae and were, therefore, microscopic carcinomas (microcarcinomas). Thus C57BL/Ha mice were not totally resistant to the neoplastic stimulus of DMH, and the susceptibility of the large intestine is site-specific in both mouse strains.

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PubMed1984

Effects of specific active immunization on tumor recurrence following primary tumor resection in WF rats with 1,2-dimethylhydrazine-induced bowel cancer.

Primary gastrointestinal tumors were induced in male WF rats by 16 weekly sc injections of 1,2-dimethylhydrazine [(DMH) CAS: 540-73-8; 20 mg/kg/wk]. Twenty-four to 28 weeks after the start of DMH injections, all rats were surgically explored and gastrointestinal tumors were resected. Rats with no remaining microscopic disease after operation were immunized with one of four tumor isografts. The first isograft, DMH-W163, is a poorly differentiated mucinous adenocarcinoma explanted from a colon cancer in a DMH-treated animal. It has been shown to possess antigens that cross-react with other DMH-induced bowel adenocarcinoma isografts. The second isograft, DMH-W49, is a carcinosarcoma explanted from a DMH-treated primary colon cancer. It has intermediate antigenic cross-reactivity with other colon adenocarcinoma isografts in the WF model. The third isograft, DMH-W15, is a sarcoma explanted from a DMH-induced colon cancer that does not possess antigens cross-reactive with other DMH-induced colon adenocarcinomas. The fourth isograft, SPK, is a spontaneous (non-DMH-induced) renal cell carcinoma that is immunogenic but should not contain tissue-type-specific antigens cross-reacting with the bowel cancers. Immunized rats received three sc weekly injections of 1 X 10(3) irradiated cells. Concomitant control rats received no immunization after resection of the primary tumor. Within 24 weeks of primary tumor resection, 12 of 16 (75%) rats not immunized had tumor recurrence. Only 8 of 24 (34%) rats immunized with DMH-W163 had tumor recurrence (P less than .025 compared to controls). Fifty percent of animals (10/20) immunized with the carcinosarcoma DMH-W49 had a recurrence. Animals immunized with the non-cross-reacting DMH-W15 sarcoma isograft had a recurrence rate similar to that of controls (16/20, 75%). The rats immunized with SPK were not protected from recurrence. Twelve of 19 (63%) had a recurrence at or near the suture line within 24 weeks following primary tumor resection. These results confirm that adjuvant immunotherapy can decrease the rate of recurrence following primary tumor resection in this model. In addition, immunogens that possessed tissue-type-specific antigens were more effective in preventing tumor recurrence than those that did not.

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PubMed1983

[Tumors induced by 1,2-dimethylhydrazine in hybrid mice with the pituitary gland transplanted in the kidney].

1,2-Dimethylhydrazine (DMH) decreased the incidence of tumors in hypophyseal isografts in hybrid mice (CBA X C57BL/6)F1 and prevented the development of mammary tumors. In mice bearing hypophyseal isografts, there was a decrease in the incidence of DMH-induced hemangiomas of the ovary. The same mice showed no alterations in the incidence of DMH-induced uterine sarcomas, tumors of the large intestine, anal region and liver.

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PubMed1984

Promotion by orotic acid of liver carcinogenesis in rats initiated by 1,2-dimethylhydrazine.

Our earlier experiments revealed that orotic acid, a precursor for pyrimidine nucleotides, selectively stimulated the growth of carcinogen-modified liver cells to grow into enzyme-altered hepatocytes (Cancer Lett., 16: 191-196, 1982). The present study was designed to determine whether prolonged feeding of orotic acid will result in hepatocellular carcinoma in initiated rats. Accordingly, groups of rats were given i.p. either 1,2-dimethylhydrazine dihydrochloride (100 mg/kg) or an equivalent volume of 0.9% sodium chloride solution 18 hr after two-thirds partial hepatectomy. After 1 week of recovery, they were continued on either the basal diet or the basal diet containing 1% orotic acid for 10 to 13 months. Some groups of rats, in addition, received a single necrogenic dose of CCl4 8 weeks following exposure to orotic acid diet. The results obtained indicated that 87.5% of initiated rats exposed to orotic acid developed hepatocellular carcinomas in 10 months and 100% in 13 months. Initiated rats exposed to orotic acid diet coupled with a single administration of CCl4 developed 100% hepatocellular carcinoma by 10 months. In contrast, the incidence of hepatocellular carcinoma in initiated rats fed basal diet alone for 13 months was 37.5%, while, in those that received CCl4 in addition, the incidence was 25% in 10 months. Interestingly, a significant number of liver cancers (29 to 36%) in the orotic acid-fed group metastasized to lungs, whereas none of the liver cancers in rats exposed to basal diet metastasized.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1982

Bile acids: effects on absorption of 1,2-dimethylhydrazine and 7,12-dimethylbenz[a]anthracene in the colon of the rat and guinea pig.

The specific effects of bile acids as cocarcinogens were investigated. Absorptions of [14C]7,12-dimethylbenz[a]anthracene, [14C]dimethylhydrazine ([14C]DMH), and [3H]inulin from loops of colons from outbred Sprague-Dawley rats and Hartley guinea pigs were determined. In each animal absorption of one carcinogen and inulin was studied in one control loop and in an experimental loop containing either deoxycholic acid (DOC) or chenodeoxycholic acid (CDOC). DOC had a more pronounced effect on increasing loss of carcinogen from the intestinal lumen than did CDOC. This role of bile acids was consistent with their known effect of increasing intestinal permeability. Less carcinogen remained in the colon mucosa when DOC was present in the intestinal lumen. Although [14C]DMH was absorbed more rapidly from the intestinal lumina of guinea pigs than from those of rats, the rat accumulated more of the carcinogen in the intestinal mucosa and liver.

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PubMed1983

Effects of 1,2-dimethylhydrazine treatment and feeding regimen on rat colonic epithelial cell proliferation.

The present study was designed to test the hypothesis that 1,2-dimethylhydrazine dihydrochloride (DMH) induces preneoplasia in rat colonic epithelium and that this DMH-altered epithelium will respond differently to various nutritional challenges in comparison to normal colonic epithelium. Preneoplasia was arbitrarily defined as an altered and irreversible state of colonic epithelial cell proliferation induced by a carcinogen (DMH). In summary, DMH was found to be specific for the enhancement of rat colonic epithelial cell proliferation compared to other rapidly renewing cell populations, i.e., ileal epithelium and ear epidermis. DMH-induced changes in rat colonic epithelial cell proliferation and crypt cellularity were found to be irreversible following a 2- to 8-week recovery period. The p.o. administration of the solid and liquid diets, regardless of chemical constituents, supported a DMH-induced increase in colonic epithelial cell proliferation; however, a DMH-induced increase in epithelial cell proliferation was not observed in rats maintained on total parenteral nutrition. Thus, the route of administration has a significant influence on epithelial cell proliferation in colonic epithelium of DMH-treated rats. The importance of these results, along with previous studies, is the establishment and initial characterization of an exploitable preneoplastic system in rat colonic epithelium. Particularly revealing was the finding that significant changes in crypt kinetic parameters induced by DMH treatment did not revert to control values following a 2- to 8-week recovery period. Based on an altered and irreversible state of colonic epithelial cell proliferation induced by DMH, it is concluded that: (a) the preneoplastic state is a committed state and is not dependent upon the continued presence of the carcinogen; and (b) all cryptal epithelium is preneoplastic, although not all cells progress to the overtly transformed state. In addition, total parenteral nutrition prevented the expression of a DMH-induced preneoplastic state of altered epithelial cell proliferation.

1,2-Dimethylhydrazine↗
PubMed1983

Effects of small bowel transection, resection, or bypass in 1,2-dimethylhydrazine-induced rat intestinal neoplasia.

The incidence, distribution, size, and histopathology of rat small and large bowel tumors induced by sequential administration of 1,2-dimethylhydrazine followed by either small bowel resection, 50% jejunoileal resection, or 50% jejunoileal bypass were examined in addition to measurements of transit times and beta-glucuronidase activities in large bowel contents. The results indicate that even limited small bowel resection or bypass promotes intestinal neoplasia, particularly in the large bowel, and this effect seems independent of the chronic injury imposed by suture lines. Although no differences in transit times were observed, increased beta-glucuronidase activities in both cecum and distal colon of resected but not bypassed rats was detected. Moreover, an apparent subsite redistribution of small bowel tumors to ileum and large bowel tumors to more proximal colon in bypassed rats suggests that the mechanisms involved for tumor enhancement differ substantially from those in resected rats.

1,2-Dimethylhydrazine↗
PubMed1983

Selenium inhibition of 1,2-dimethylhydrazine-induced colon carcinogenesis.

The inhibitory effect of selenium (Na2SeO3) on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in male Sprague-Dawley rats is presented. A 4-ppm selenium supplement to the drinking water was provided concurrently with DMH treatment and continued until death or sacrifice. Rats were administered 10 weekly injections of 10 mg DMH per kg body weight. Thirtyone weeks following the tenth DMH injection, all surviving animals were sacrificed. At sacrifice, the colon tumor incidence in DMH-only controls was 8 of 28 (29%). Selenium supplementation significantly (p less than 0.01) reduced the colon tumor incidence to 1 of 37 (3%). The cumulative colon tumor incidence for all animals found dead or sacrificed was also significantly (p less than 0.05) reduced from 11 of 40 in DMH controls to 3 of 40 in DMH-selenium-supplemented rats. The total number of colon tumors was reduced from 13 to 3, and the average number of tumors per rat from 1.2 to 1.0 by supplemental selenium. The majority (greater than 65%) of all tumors were located in the distal colon. The serum glutamic oxaloacetic transaminase, alkaline phosphatase, and complete blood count were normal and equivalent for the DMH only, DMH-selenium, and untreated control groups in this study. The glutathione S-transferase activity in liver cytosol preparations was increased from 39.6 +/- 7.3 (S.D.) microM product/min/mg (DMH only) to 67.6 +/- 5.8 microM product/min/mg by selenium only and to 54.3 +/- 10.6 microM product/min/mg in selenium-DMH-treated rats. Protection by selenium may in part be attributed to enhanced detoxification of carcinogenic electrophiles.

1,2-Dimethylhydrazine↗
PubMed1983

[Influence of the rhythm and route of 1,2-dimethylhydrazine administration on its carcinogenic effect in mice].

Effects of route of administration (subcutaneous, intraperitoneal, by stomach tube and with drinking water) and dose fractionation on the carcinogenicity of 1,2-dimethylhydrazine (DMH) were studied in CBA and (C57B1/6j X CBA)F1 mice. Fractionation of DMH dose given subcutaneously exerted different effects on tumors at various sites: decrease of colon and anal tumor incidence, increase of vascular liver tumors and renal adenomas and no influence on hepatoma, lung adenoma and uterine sarcoma induction. When given with drinking water, DMH did not induce colon and anal tumors but produced high incidence of vascular neoplasms. No such effect was observed when DMH was administered weekly by stomach tube. Alteration of the organotropism of DMH given with drinking water is attributed by authors to the decrease of single DMH dose and not to peroral route of administration.

1,2-Dimethylhydrazine↗
PubMedDate not supplied

The carcinogenic effect of intracolonic administration of 1,2-dimethylhydrazine dihydrochloride in mice.

1,2-Dimethylhydrazine dihydrochloride (1,2-DMH) was given to Swiss mice in 1 or 10 weekly intracolonic instillations of 60 and 40 micrograms/g body weight, respectively. In mice that received a single treatment, the tumor incidences in the lungs, blood vessels and subcutis were 34% (p less than 0.006), 8 and 25 in females and 2, 20 and 0% in males, respectively. In mice treated repeatedly with the carcinogen, the corresponding tumor incidences were 34% (p less than 0.006), 38% (p less than 0.000001) and 12% (p less than 0.03) in females and 34, 10 and 0% in males, respectively. In control mice the tumor incidences in lungs, blood vessels and subcutis were 15, 8 and 2% in females and 22, 5 and 2% in males, respectively. The induction of large intestinal cancer, which was the main objective of this investigation, however, failed to materialize.

1,2-Dimethylhydrazine↗
PubMed1982

Aberrant and nonrandom methylation of chromosomal DNA-binding proteins of colonic epithelial cells by 1,2-dimethylhydrazine.

The alkylating carcinogen 1,2-dimethylhydrazine (DMH) induces colonic tumors with high incidence. The sites of in vivo modification of target macromolecules were studied using [methyl-3H]DMH. Carcinogen binding to subcellular fractions of colonic epithelial cells was analyzed at time intervals ranging from 10 min to 36 hr, with particular emphasis on the alkylation of nuclear constituents. DMH modifies not only nucleic acids but also histones and other DNA-binding proteins in the target cells. Separation of the 3H-methylated amino acids showed aberrant methylation patterns after exposure to [3H]DMH, as compared with methylations observed with [methyl-3H]methionine as a natural methyl group donor. DMH-modified histone H1 contained methylated lysin, arginine, and histidine residues not normally found, and other histones had abnormal methylarginine contents. High-mobility-group proteins and other nuclear proteins contained methyllysine residues not normally detected. Proteins known to be associated with template-active and more accessible DNA sequences, such as the high-mobility group proteins and the multiacetylated forms of histones H3 and H4, were preferentially damaged after exposure to [3H]DmH. The result suggests that carcinogen-induced chromosomal damage is not random and may selectively affect proteins in the actively transcribing or replicating genes in the target cells. That damage affects the amino acids most likely to be involved in DNA binding.

1,2-Dimethylhydrazine↗
PubMed1981

Changes in crypt cell populations of mouse colon during recovery from treatment with 1,2-dimethylhydrazine.

The induction of adenocarcinomas in distal colons of noninbred female Swiss Webster white mice by 1,2-dimethylhydrazine (DMH) is preceded by the development of hyperplasia of mucosal glands, which includes absolute increases in both the total number of cells and labeled cells per crypt. This experiment was designed to determine if these changes are reversible. Groups of noninbred female Swiss Webster white mice were given weekly injections of DMH, 20 mg/kg body weight, for 1--20 weeks and killed 1--52 weeks after treatment. Animals were pulsed with tritiated thymidine ([3H]dTHd) for 1 hour and autoradiographs were made of sections of distal colon. The total number of cells per crypt and number of [3H]dThd-labeled cells per crypt were significantly elevated in animals killed 1 week after termination of treatment. With increasingly longer periods of recovery, base-line values were reached rapidly in animals given one or two treatments; however, reduction in cells was slower and less complete in animals given eight or more treatments. The latency before tumors developed was inversely related to the number of treatments. Animals that received 20 treatments developed more tumors per tumor-bearing animal than did animals given fewer treatments but allowed by survive for long periods. The findings indicate that once induced changes in the mucosa progress to a threshold level, mucosal glands are irreversibly enlarged and the development of tumors is irrevocable.

1,2-Dimethylhydrazine↗
PubMed1982

Effects of sublethal irradiation on changes in crypts of the mouse colon during treatment with 1,2-dimethylhydrazine.

The effects of low-dose X-irradiation on the progression of early neoplastic changes induced in the colon by 1,2-dimethylhydrazine (DMH) were assessed. Outbred female Swiss-Webster mice were treated with DMH only, DMH-irradiation, irradiation only, or 0.001 M EDTA. Animals were pulsed with [3H]thymidine for 1 hour, and the distal colon was radioautographed. The number of labeled cells per crypt in animals tested with DMH-irradiation was greater (P less than 0.01) than the number in "DMH-only" animals, but a corresponding increase in the length of the crypts did not occur. After 16 weeks of treatment, the percentage of animals with focal atypia was similar in the DMH-irradiation group (87%), and the DMH-only group (100%), but there were more focal atypias per animal in the DMH-only group. After 20 weeks, 14% of the DMH-irradiation group had visible tumors compared to 63% of the DMH-only group. The results suggest that DMH increased the number of cells at risk for irradiation; thus the surge in proliferation subsequent to cell depletion was amplified. However, the development of precancerous lesions was not promoted.

1,2-Dimethylhydrazine↗
PubMed1982

Cell specificity in hepatocarcinogenesis: preferential accumulation of O6-methylguanine in target cell DNA during continuous exposure to rats to 1,2-dimethylhydrazine.

Concentrations of the major methylated DNA purines were determined in two liver cell cell populations of Fischer 344 rats during administration of 30 ppm 1,2-dimethylhydrazine (SDMH) in the drinking water for periods of up to 4 weeks. Quantitation of 7-methylguanine and O6-methylguanine (O6MG) was achieved by highly sensitive optical methods following separation of DNA bases by high-performance liquid chromatography. Overall alkylation as indicated by the concentration of 7-methylguanine was near maximum in both hepatocytes and liver nonparenchymal cells by the third day of SDMH administration. Similar amounts of 7-methylguanine were present in the two liver cell populations at seven of nine time points during 4 weeks of exposure. In contrast, dramatic differences in the cumulative concentrations of O6MG were seen in the two cell populations. Nonparenchymal cells accumulated O6MG during the first 8 days of exposure and had up to a 30-fold greater concentration of this product than did the corresponding hepatocytes. In the hepatocytes, a rapid decline in O6MG concentration was observed between 1 and 3 days of exposure to SDMH. Thereafter, only low levels of this promutagenic lesion were present in hepatocytes. Exposure of rats to the same regimen of SDMH for up to 10 months caused angiosarcomas in the livers of over 90% of the animals, while hepatocellular carcinomas occurred in only 40%. Thus, a strong correlation exists between the inability to repair O6MG and cell specificity for carcinogenesis.

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PubMed1982

Region-specific patterns of mucin reaction demonstrated by paradoxical concanavalin A-staining in normal colonic epithelium and in colorectal cancers induced in rats by 1,2-dimethylhydrazine.

The histochemistry of mucin in normal large intestine and in experimental colorectal cancers induced in Wistar rats with 1,2-dimethylhydrazine was analyzed by modifications of the concanavalin A-horseradish peroxidase method (paradoxical concanavalin A-staining) and high-iron diamine-Alcian blue (pH 2.5) staining (HID-AB). Quantitative analysis of each mucin reaction was done by the use of an image analyzer. Regional variations in the percentage area of "labile class III mucin" were 1 to 50% in the distal colon and 50 to 90% in the proximal colon. Regional variations in the percentage area of sulfated sialomucin were 80 approximately 100% in the distal colon and under 20% in the proximal colon. The percentage area of "labile class III mucin" in primary colorectal cancers showed region-specific variation and that in metastatic colorectal cancers also showed similar region-specific variation of colorectal mucosa where primary tumors were located. In contrast, there were no region-specific mucin reactions for sulfated sialomucin in almost all primary and metastatic colorectal cancers.

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