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PubMed1988

Species-specific response to the rodent carcinogens 1,2-dimethylhydrazine and 1,2-dibromo-3-chloropropane in rodent bone-marrow micronucleus assays.

1,2-Dimethylhydrazine is confirmed as active in the mouse bone-marrow micronucleus assay when administered as an aqueous solution via oral gavage to three different strains of mice. It is also shown to be inactive in a corresponding rat assay under similar conditions of test. The observations were independently repeated in two laboratories. In contrast, 1,2-dibromo-3-chloropropane showed the reverse profile, being active in the rat bone-marrow assay but inactive in the mouse; the latter observations were also made in two laboratories. The carcinogen procarbazine was active in both species. These findings are discussed within the context of the present GeneTox revision of the standard test protocol of the rodent bone-marrow micronucleus assay.

1,2-Dimethylhydrazine↗
PubMed1988

DNA ploidy in 1,2-dimethylhydrazine-induced rat tumors.

The DNA content of 1,2-dimethylhydrazine (DMH)-induced intestinal tumors of male Wistar rats was analyzed by using flow cytometry. All adenomas and carcinomas were DNA diploid. S-phase fractions of tumors showed no significant difference from those of normal mucosae. Histological evidence of adenoma-carcinoma sequence was observed in our series. The lack of DNA aneuploidy is one of the principal differences between the DMH model and human colorectal cancers.

1,2-Dimethylhydrazine↗
PubMed1988

Activated K-ras in tumorigenic and non-tumorigenic cell variants from a rat colon adenocarcinoma, induced by dimethylhydrazine.

Using NIH3T3 cell transfection assay, activated c-K-ras was detected in two cell lines, TRb and TSb, obtained from a single colon adenocarcinoma induced in a rat by 1,2-dimethylhydrazine. TRb cells give rise to progressive and metastatic tumors in the syngeneic rats, whereas TSb cells only induce regressive tumors. Levels of K-ras transcripts in TRb and TSb cells were higher than that of NIH3T3 cells, but no difference was found between TRb and TSb cells. No significant difference was observed in expression levels of c-myc in these two cell lines. c-fos expression was, however, significantly lower in TRb than TSb cells.

1,2-Dimethylhydrazine↗
PubMed1992

Tumor induction in monkeys after administration of dimethylhydrazine.

1,2-Dimethylhydrazine (DMH) was administered subcutaneously to nine Macaca fascicularis monkeys (6 males and 3 females) at doses of 16 mg/kg body weight, three times a month for two years. Colon cancer was detected in two male monkeys after total DMH doses of 1080 and 3696 mg (528 and 400 mg/kg body wt., respectively). A uterine tumor was induced in one female monkey which received 3648 mg of DMH (608 mg/kg body wt.). Latent periods of tumor development were 34, 47 and 55 weeks, respectively. Histologically, the colon tumors had the structure of adenocarcinoma in both cases and the uterine tumor was diagnosed as fibromyoma.

1,2-Dimethylhydrazine↗
PubMed1992

Carcinogenicity of 1,2-dimethylhydrazine in colorectal tissue heterotopically transplanted into the glandular stomach of rats.

The present study was designed to examine the effect of the intestinal carcinogen 1,2-dimethylhydrazine (DMH) on grafted colorectal mucosa implanted into the glandular stomach of rats. Four groups were studied: Group 1 received the operation and DMH, Group 2 received the operation alone, Group 3 received DMH alone and Group 4 (controls) received only a sham operation. For Groups 1 and 2, about 8-mm diameter segments of colorectal tissue obtained from various sites in the large intestine of 8-week-old male F344 rats were isologously implanted into the fundic region of the stomachs of age-matched rats. DMH was injected at a dose of 20 mg/kg body weight i.m. per week for 20 weeks beginning 4 weeks after the operation. The animals were then observed for 8 months after the initial DMH treatment. In Group 1, adenocarcinomas developed in 41 of 60 successful implants (68%). Furthermore, poorly differentiated type tumors were observed in the grafts obtained from the rectum. This finding was contrary to that for intrinsic rectal tumors, all of which were well differentiated. The histochemical staining of mucin in the tissues from different sites of the large intestine revealed that sulfomucin, which normally exists essentially only in the intrinsic descending colon or rectum, was present in the grafts from the proximal ascending or ascending colon. No gastric tumors were observed in the control rats, which received either DMH or sham operations alone. Tumors in the intrinsic large intestine were observed only in rats that received DMH. These results indicate that colorectal mucosa implanted into the glandular stomach, like the intrinsic large intestine, is still sensitive to tumorigenesis caused by DMH.

1,2-Dimethylhydrazine↗
PubMed1995

Inhibition of 1,2-dimethylhydrazine-induced oxidative DNA damage by green tea extract in rat.

Following subcutaneous injection of 1,2-dimethylhydrazine (DMH), which is carcinogenic to rat colon and liver, to Sprague-Dawley rats, a significant increase of 8-hydroxydeoxyguanosine (8-OHdG) was observed in the DNA of colonic mucosa and liver. The 8-OHdG formation reached the maximal level at about 24 h after the DMII injection. On the other hand, no increase of 8-OHdG was observed in the DNA of the kidney. Drinking green tea extract (GTE) for ten days prior to the DMH injection significantly inhibited the formation of 8-OHdG in the colon. These findings demonstrate that DMH causes oxidative damage to the DNA of its target organ, and that GTE protects colonic mucosa from this oxidative damage.

1,2-Dimethylhydrazine↗
PubMed1996

Gastric tumorigenicity of 1,2-dimethylhydrazine on the background of gastric intestinal metaplasia induced by X-irradiation in CD (SD) rats.

Five-week-old male CD (SD) rats were X-irradiated with a total of 20 Gy in 2 equal fractions with a 3-day interval. After the second irradiation, rats were fed normal diet supplemented with 1% sodium chloride, which is known to increase intestinal metaplasia. 1,2-Dimethylhydrazine (DMH) solution was injected i.m. into the back musculature at a dose of 20 mg/kg body weight weekly for 10 weeks, beginning 20 weeks after the final irradiation. Twelve months after the initial carcinogen treatment, gastric tumors in the glandular stomach were observed in 2 (3 lesions) of 30 animals in the X-irradiated and DMH-treated group fed diet supplemented with 1% sodium chloride. No gastric tumors were observed in the group which excluded X-irradiation from the experimental protocol.

1,2-Dimethylhydrazine↗
PubMed1996

Aspirin suppresses 1,2-dimethylhydrazine-induced alteration of proliferative parameters in rat colonic crypts.

Human epidemiological reports and rodent experimental research data indicate a possible chemopreventive effect of regular aspirin use for decreasing risk of colon and rectum cancer incidence and mortality. We have previously demonstrated that aspirin can significantly suppress proliferative parameters in normal rat colonic epithelium when examined 24 h following an acute or chronic course of aspirin administration. To investigate whether aspirin would effectively suppress known carcinogen-induced changes in colonic epithelium, rats were given single s.c. injections of either aspirin (50 mg/kg bw) or saline on days 1-3 and either 1,2-dimethylhydrazine (DMH; 12 mg base/kg bw) or DMH vehicle on day 4 of each week for eight consecutive weeks. Rats were sacrificed 4 days after the last aspirin dose and 3 days after the last DMH or DMH vehicle dose. Using the proliferative biomarkers of proliferating cell nuclear antigen positive cells per midaxial crypt section (SCC), crypt proliferative zone height (PZ), crypt differentiated zone height (DZ), and total crypt height (CH), it was found that aspirin does suppress DMH-induced increases in SCC, PZ and CH. The findings demonstrate that aspirin has a long term (i.e. several days) protective effect against early carcinogen-induced proliferative changes in rat colonic crypts which may help account for aspirin's chemopreventive action against colon cancer.

1,2-Dimethylhydrazine↗
PubMed1982

Pathogenesis of 1,2-dimethylhydrazine-induced carcinomas in rat intestine. I. The induction of mucin producing carcinomas in rat intestine.

Seventy four white male Wistar rats were divided into two groups and given weekly subcutaneous injections of 30 mg 1,2-dimethylhydrazine (DMH) 2HC1/kg body weight for 10 or 15 weeks, respectively, and the histological properties and distribution of DMH-induced rat carcinomas were investigated. The carcinomas induced by DMH were classified mainly into mucin producing carcinomas and non-mucin producing ones. In the large intestine, the group treated for 15 weeks induced significant incidences of mucin producing carcinomas composed mainly of cells containing intracellular mucin. Mucin producing carcinomas consisted of poorly differentiated adenocarcinoma, signet ring cell carcinoma and mucinous carcinoma, and these often coexisted within the same tumor mass. Mucin producing carcinomas tended to develop in the proximal colon and caecum, while non-mucin producing carcinomas were frequent in the distal colon. This method was thought to be a useful model to study glycoproteins of cancer cells.

1,2-Dimethylhydrazine↗
PubMed1983

Combination chemotherapy with 5-fluorouracil (5FU) and 1,3-bis(2-chloro-ethyl)-1-nitrosourea (BCNU) prolongs survival of rats with dimethylhydrazine-induced colon cancer.

The effects of combination chemotherapy with 5FU and BCNU on rats with dimethylhydrazine (DMH)-induced colon cancer were investigated in a long term survival study. Eighty Wistar rats received a colon cancer producing regimen on DMH (40 mg/kg body weight/week, subcutaneously for 10 weeks). After presenting with signs of colonic disease, all rats underwent diagnostic laparotomy and colonoscopy when colon tumours were located, measured and the extent of the disease staged. Only animals with tumours (n = 63) were included and allocated to one of three tumour stages. Stage A (n = 17), had colonic tumours without serosal involvement; stage B (n = 28) had serosal involvement without metastases; stage C (n = 18) had serosal involvement with lymphadenopathy and/or metastases. Each group was randomly allocated into two subgroups, one serving as untreated controls while the other received 5FU (300 mg/m2 weekly intragastrically for life) together with BCNU (40 mg/m2 intraperitoneally on days 0, 42 and 84). The effect of chemotherapy on tumour growth was measured sequentially by colonoscopy. Animals were observed until death and necropsied, when colon carcinoma was histologically confirmed and survival analysed. The results indicate that chemotherapy significantly prolongs the survival of rats with the least advanced disease (stage A) but was of no benefit to rats with locally advanced or metastatic disease (stages B and C). Furthermore, chemotherapy was associated with a significant reduction in tumour size. Survival analyses in untreated animals show that the laparotomy staging system adopted provides accurate prognostic information. This study shows that DMH-induced colon tumours are chemosensitive, and suggests that this animal model may be a valuable testing ground for new chemotherapeutic agents.

1,2-Dimethylhydrazine↗
PubMed1982

Subtotal colectomy in the dimethylhydrazine-treated rat. A surgical model of colorectal cancer.

The effects of subtotal colectomy on the survival of rats with established colon cancer induced by 1,2-dimethylhydrazine (DMH) have been investigated in an attempt to assess whether it might provide a suitable model of surgical treatment of this disease. 40 female Wistar rats received a regimen of DMH injections (40 mg/kg body weight s.c. every 14 days for 10 weeks) known to produce colon cancer. An additional 10 rats received no DMH, serving as controls (group 1). After presenting with signs of colonic disease at 25 weeks, all DMH-treated rats had diagnostic colonoscopy under general anaesthesia, only those with visible neoplasms (n = 34) being included in the study. These were randomised into two groups: group 2 (n = 13) animals were unoperated controls while group 3 (n = 21) animals had a therapeutic subtotal colectomy with histological confirmation of cancer in the resected colon. The animals were observed until death, the postoperative survival and cause of death at necropsy being compared between groups. The results showed that overall survival (p less than 0.013) and survival from death due to colon cancer (p less than 0.001) were significantly increased in the colectomised group 3 animals compared to unoperated controls (group 2). While 91% of the unoperated controls died of colon cancer, only 8% of the colectomised group died of this cause (p less than 0.001), the remainder dying from unrelated causes, predominantly DMH-induced primary extracolonic cancers. Subtotal colectomy in rats with DMH-induced colon cancer reduces mortality from this disease, providing a suitable model of surgical treatment. However, the high incidence of DMH-induced extracolonic cancers may make the model unsuitable for studies of adjuvant therapy.

1,2-Dimethylhydrazine↗
PubMed1989

1,2-Dimethylhydrazine-induced carcinogenesis influenced by different colonic anastomoses in rats.

Dispensing subcutaneously 1,2-dimethylhydrazine, intestinal carcinogenesis was investigated in male Fisher rats with different surgical colonic anastomoses, producing blind gut loops of isoperistaltic high (fecal stasis) and anisoperistaltic low fecal contact. One hundred and eight rats, except 1 rat of the control group, developed colonic neoplasms. In contrast to the control group, mainly in anastomotic areas and in isoperistaltic blind gut loops with intensive fecal contact huge adenocarcinomas of exophytic growth appeared with a mean tumor diameter (MTD) of 1.9 +/- 0.7 to 2.2 +/- 0.8 cm. Even in the control group, where rats only underwent laparotomy, we observed small polypoid adenocarcinomas mainly located in the distal colon (MTD: 0.7 +/- 0.3 cm). Anastomotic areas and isoperistaltic blind loops with intensive fecal contact proved to be regions with a higher risk for carcinoma formation.

1,2-Dimethylhydrazine↗
PubMed1993

Sennosides and aloin do not promote dimethylhydrazine-induced colorectal tumors in mice.

In a model of dimethylhydrazine-induced colorectal tumors in male mice aloin- or sennoside-enriched diets (0.03%) did not promote incidence and growth of adenomas and carcinomas after 20 weeks. Furthermore, in anthranoid-fed mice no significant changes in serum electrolytes as well as parameters of hepato- and nephrotoxicity were observed.

1,2-Dimethylhydrazine↗
PubMed1986

Premalignant alterations in the lipid composition and fluidity of colonic brush border membranes of rats administered 1,2 dimethylhydrazine.

Dimethylhydrazine (DMH) is a potent procarcinogen with selectivity for the colon. To determine whether alterations in the lipid composition and fluidity of rat colonic brush border membranes existed before the development of DMH-induced colon cancer, rats were injected s.c. with this agent (20 mg/kg body weight per wk) or diluent for 5, 10, and 15 wk. Animals were killed at these time periods and brush border membranes were prepared from proximal and distal colonocytes of each group. The "static" and "dynamic" components of fluidity of each membrane were then assessed, by steady-state fluorescence polarization techniques using limiting hindered fluorescence anisotropy and order parameter values of the fluorophore 1,6 diphenyl-1,3,5-hexatriene (DPH) and fluorescence anisotropy values of DL-2-(9-anthroyl) stearic acid and DL-12-(9-anthroyl) stearic acid, respectively. Membrane lipids were extracted and analyzed by thin-layer chromatography and gas-liquid chromatography. Phospholipid methylation activity in these membranes was also measured using S-adenosyl-L-methionine as the methyl donor. The results of these studies demonstrate that: the lipid composition and both components of fluidity of proximal DMH-treated and control membranes and their liposomes were similar at all time periods examined; at 5, 10, and 15 wk the "dynamic component of fluidity" of distal DMH-treated membranes and their liposomes was found to be higher, similar, and lower, respectively, than their control counterparts; the "static component of fluidity" of distal DMH-treated membranes and their liposomes, however, was similar to control preparations at all three time periods; and alterations in the lipid composition and phospholipid methylation activities appeared to be responsible for these differences in the "dynamic component of fluidity" at these various time periods.

1,2-Dimethylhydrazine↗
PubMed1991

Mutations in the K-ras oncogene induced by 1,2-dimethylhydrazine in preneoplastic and neoplastic rat colonic mucosa.

These experiments were conducted to determine whether point mutations activating K-ras or H-ras oncogenes, induced by the procarcinogen 1,2-dimethylhydrazine (DMH), were detectable in preneoplastic or neoplastic rat colonic mucosa. Rats were injected weekly with diluent or DMH at 20 mg/kg body wt for 5, 10, 15, or 25 wk, killed, and their colons dissected. DNA was extracted from diluent-injected control animals, histologically normal colonic mucosa from carcinogen-treated animals, and from carcinomas. Ras mutations were characterized by differential hybridization using allele-specific oligonucleotide probes to polymerase chain reaction--amplified DNA, and confirmed by DNA sequencing. While no H-ras mutations were detectable in any group, K-ras (G to A) mutations were found in 66% of DMH-induced colon carcinomas. These mutations were at the second nucleotide of codons 12 or 13 or the first nucleotide of codon 59 of the K-ras gene. The same type of K-ras mutations were observed in premalignant colonic mucosa from 2 out of 11 rats as early as 15 wk after beginning carcinogen injections when no dysplasia, adenomas, or carcinomas were histologically evident, suggesting that ras mutation may be an early event in colon carcinogenesis.

1,2-Dimethylhydrazine↗
PubMed1992

Renal cell tumors induced in CBA male mice by 1,2-dimethylhydrazine.

Epithelial kidney tumors induced in CBA male mice by 1,2-dimethylhydrazine (DMH) were studied histochemically and immunohistochemically. A total of 48 tumors studied histologically were diagnosed as clear-cell, acidophilic, or mixed adenomas located in the renal cortex. Gamma-glutamyl transpeptidase (GGT) was strongly positive in normal proximal convoluted tubules, slightly positive in the cells of Bowman's capsule, and negative in 47 of 48 tumors examined. Antibodies against the new antigen obtained from the mouse liver oval cells, antigen A6, were also used. This antigen is negative in normal kidney proximal tubules but always positive in distal tubules and collecting ducts. It was also positive in all 47 GGT-negative tumors studied here. One tumor was GGT-positive and antigen A6-negative. Based on our data, it was concluded that the majority of renal cell adenomas induced by DMH in mice probably originate from the distal tubules or collecting ducts and not from the proximal tubules.

1,2-Dimethylhydrazine↗
PubMedDate not supplied

Enzymic pattern of preneoplastic and neoplastic lesions induced in the kidney of CBA mice by 1,2-dimethylhydrazine.

Mouse renal cell tumors (RCTs) were induced in male CBA mice by 5 subcutaneous injections of 8 mg 1,2-dimethylhydrazine (DMH)/kg body weight once a week. After a lag period of 2 yr kidneys were removed, and serial cryostat sections of the kidneys were histochemically analyzed for the following parameters: glycogen content, basophilia, and the activities of glycogen synthase (SYN), glycogen phosphorylase (PHO), glucose-6-phosphatase (G6Pase), glucose-6-phosphate dehydrogenase (G6PDH), hexokinase (HK), pyruvate kinase (PK), lactate dehydrogenase (LDH), malic enzyme (ME), succinate dehydrogenase (SDH), alkaline phosphatase (ALPase) and gamma-glutamyltranspeptidase (GGT). RCTs displayed the same histochemical profile irrespective of their size and growth pattern. In comparison with the normal kidney epithelium, the neoplastic cells exhibited elevated activities of enzymes for glycolysis (HK, PK, LDH) and the pentose phosphate pathway (G6PDH), while negative G6Pase and low SDH activity were observed in these cells. The majority of RCTs showed high PHO activity and weak staining for SYN. Activities of ALPase and GGT were negative in most of the RCTs. Markedly enlarged cells with atypical nuclei were detected in some advanced RCTs. Higher activities of glycolytic and mitochondrial enzymes and G6PDH were found in these enlarged cells than in other tumor cells. Tubular preneoplastic lesions were similar to neoplastic lesions in morphological and histochemical characteristics. The present study revealed that a markedly elevated capacity for glycolysis and the pentose phosphate pathway occurred in RCTs in mice. A similar histochemical pattern in the few preneoplastic tubular lesions observed suggests that these metabolic aberrations emerge early during carcinogenesis, but additional studies on early stages of renal carcinogenesis are needed to substantiate this assumption.

1,2-Dimethylhydrazine↗
PubMed1983

Lectin histochemistry of 1,2-dimethylhydrazine-induced rat colon neoplasia.

Lectins linked to fluorescein were used as carbohydrate probes to examine the goblet cell mucin and epithelial cell surface glycoconjugate alterations in an experimental rodent model of colonic neoplasia induced with parenteral 1,2-dimethylhydrazine dihydrochloride. Lectins derived from Triticum vulgare (WGA), Ricinus communis (RCA1), and Limulus polyphemus (LPA) showed reduced labeling of goblet cell mucin in these tumors, while binding with peanut lectin from Arachis hypogaea (PNA), a lectin ordinarily failing to bind to mucin in normal colon, was positive. In addition, RCA1 and LPA showed increased cell surface labeling of neoplastic epithelial cells. Finally, alterations were observed in lectin binding to "transitional" colonic mucosa adjacent to colonic tumors from carcinogen-treated rats. These findings indicate that significant alterations in both membrane and mucin glycoconjugates occur in colonic tumors and mucosa adjacent to tumors in a chemically induced experimental animal model of human colon cancer.

1,2-Dimethylhydrazine↗