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PubMed1997

Methylnitrosourea-induced tumorigenesis in MGMT gene knockout mice.

Gene targeting was used to obtain mice defective in the MGMT gene, encoding O6-methylguanine-DNA methyltransferase [Tsuzuki et al., Carcinogenesis (Lond.), 17: 1215-1220, 1996]. These MGMT-/- mice were most sensitive to the alkylating carcinogen, methylnitrosourea; when varied doses of methylnitrosourea were administered to 6-week-old mice and survivals at the 30th day were determined, LD50s of MGMT-/- and MGMT+/+ mice were 20 and 240 mg/kg of body weight, respectively. MGMT+/- mice were as resistant as MGMT+/+ mice, but some difference in survival time was noted when the two genotypes of mice were exposed to a relatively high dose of methylnitrosourea. A large number of thymic lymphomas, as well as lung adenomas, occurred in MGMT-/- mice exposed to methylnitrosourea at a dose of 2.5 mg/kg of body weight. In case of exposure to the same dose of drug, no or few tumors occurred in the MGMT+/+ and MGMT+/- mice. It appears that the DNA repair methyltransferase protein protected these mice from methylnitrosourea-induced tumorigenesis.

Animals↗

PubMed1984

DNA damage and repair in mouse embryos following treatment transplacentally with methylnitrosourea and methylmethanesulfonate.

Mouse embryos were labeled in vivo at 10 1/2-12 1/2 days of gestation with [3H]-thymidine and subjected to DNA damage using x-ray, methylmethanesulfonate, or methylnitrosourea. DNA damage and its repair were assessed in specific cell preparations from embryos isolated at intervals thereafter using the highly sensitive method of nucleoid sedimentation, which evaluates the supercoiled state of the DNA. Repair of x-ray damage was demonstrated using trypsin-dispersed cells from whole embryos and from homogenized embryonic liver to show the validity of the analytical approach. The effects of the highly teratogenic methylnitrosourea and the much less teratogenic methylmethanesulfonate were compared in the targeted limb buds using equitoxic doses of the two alkylating agents. DNA supercoiling was fully restored after 24 hr in limb bud cells damaged with methylmethanesulfonate, while as much as 48 hr were required for full repair of methylnitrosourea damage. These results demonstrated the feasibility of studying DNA repair in embryonic tissues after damage in vivo and suggest that the potency of methylnitrosourea as a teratogen may be correlated with a prolonged period required for complete repair of DNA.

Animals↗

PubMed1981

Induction of retinal degeneration in cats by methylnitrosourea and ketamine hydrochloride.

Persistent mydriasis seen in cats used in an oncology study apparently was not related to neoplasia. Ophthalmoscopically, the cats had severely atrophic retinas and clinically observable visual impairment. These findings were confirmed by electroretinographic and histologic examination. Cats with these retinal lesions had received combinations of methylnitrosourea, ketamine hydrochloride, and feline leukemia virus. Retinopathy was not seen in ketamine-anesthetized cats receiving feline leukemia virus. To test the nature of this phenomenon, four cats were given both drugs and three received methylnitrosourea alone. The four cats developed severe generalized retinal degeneration by day 5, whereas the three cats given methylnitrosourea alone had normal retinas. Histologic changes in the affected cats were extensive loss of rods and cones, and of the outer nuclear layer. The electroretinographic responses to white light were depressed or extinguished. Retinal degeneration, therefore, appeared to be dependent upon administration of both methylnitrosourea and ketamine hydrochloride.

Animals↗

PubMed1978

Increased susceptibility to feline leukemia virus infection in cats exposed to methylnitrosourea.

Exposure of adult specific-pathogen-free cats to methylnitrosourea resulted in increased susceptibility to infection by feline leukemia virus. A greater proportion of cats exposed to methylnitrosourea and feline leukemia virus (69%) became persistently viremic than those exposed to feline leukemia virus alone (17%). Segmented neutrophils were reduced by 90 to 99% within 3 days following exposure to methylnitrosourea, (15 to 20 mg/kg) whereas the effects on lymphocytes and erythrocytes, although less obvious, were also detected.

Animals↗

PubMed1979

Biochemical evidence of cocarcinogenesis: tumor promoting agent enhances methylnitrosourea activation of rat guanylate cyclase activity.

The two-stage or cocarcinogenic hypothesis of carcinogenesis involves an initiator (carcinogen) and a promotor (cocarcinogen) being utilized in combination to produce more tumors than either would alone. This theory was tested at the cellular level utilizing Tumor Promoting Agent, 12-0-tetradecanoly-phorbol-13-acetate, (promotor) in combination with submaximal and maximal doses of methylnitrosourea (initiator). Tumor promoting agent, which can cause some tumors itself, was found to enhance the activity of guanylate cyclase (E.C.4.6.1.2.), an enzyme that has been associated with normal and abnormal growth. Tumor promoting agent when utilized in combination with submaximal stimulatory doses of methylnitrosourea had an additive effect on guanylate cyclase activity, but the agent had no further additive effect on guanylate cyclase activation when methylnitrosourea was utilized in maximal stimulatory doses. These results indicate a carcinogen acting alone without a promoter can maximally activate guanylate cyclase and would suggest that at the cellular level a promotor is not absolutely necessary for the changes observed morphologically in canerous cells. The promotor, however, did enhance the enzyme's activity when a submaximal dose of the carcinogen was used indicating that promoting agents, at least biochemically, appear capable of potentially contributing to the development of a cancerous cell.

Animals↗

PubMed1982

Participation of poly(ADP-ribosyl)ation in the depression of RNA synthesis caused by treatment of mouse lymphoma cells with methylnitrosourea.

When mouse lymphoma cells (L-1210) are treated with methylnitrosourea, a DNA-damaging agent, polyadenosine diphosphoribose (poly(ADP-ribose)) synthetase activity increases 5-8-fold in 2-3 h, while RNA polymerase activity remains constant for an initial 2 h and then gradually decreases to 25-30% of the control level in 5 h. Both alpha-amanitin-sensitive and -resistant RNA polymerase activities are depressed to the same degree by the treatment with methylnitrosourea. The depression in RNA synthesis is virtually prevented when the treated cells are cultured in the presence of 3-aminobenzamide, a specific inhibitor of poly(ADP-ribose) synthetase. Analyses of the RNA extracted from the cells labeled with [3H]uridine by agarose gel electrophoresis and by poly(U)-Sepharose column chromatography show that the contents of ribosomal precursor RNA and poly(A)-containing RNA are both low in the methylnitrosourea-treated cells as compared with those in the untreated cells and that the reduction in the contents of these kinds of RNA is almost completely prevented by the addition of 3-aminobenzamide to the culture medium. These results suggest that the enhancement of poly(ADP-ribosyl)ation causes the decrease in both synthesis of ribosomal RNA and messenger RNA.

Animals↗

PubMed1985

Influence of experimental diets on hepatic glutathione levels in rats with methylnitrosourea-induced mammary carcinoma.

Mammary tumor development induced by methylnitrosourea in female Sprague-Dawley rats had no significant effect on hepatic glutathione levels. If the diets of methylnitrosourea-treated animals were supplemented with vitamin A and E an increased hepatic glutathione level was observed initially. A high fat diet (21% per weight) supplemented with the two vitamins led to a decreased hepatic glutathione level 2 months after tumor induction. Advanced tumor development under any of the diets tested had no effect on hepatic glutathione.

Animals↗

PubMed2003

Prevention by intrarectal 5-aminosalicylic acid of N-methylnitrosourea-induced colon cancer in F344 rats.

PURPOSE: The protective effect of 5-aminosalicylic acid against colon carcinogenesis was investigated. METHODS: Eighty female F344 rats aged seven weeks received an intrarectal dose of 2 mg N-methylnitrosourea dissolved in 0.5 ml of water three times weekly for five weeks to induce colon cancer. Beginning at 6 weeks after the last dose of N-methylnitrosourea, the rats were treated with an intrarectal dose of 1 mg 5-aminosalicylic acid suspended in 0.5 ml of vehicle solution (0.3 percent water solution of methylcellulose) three times weekly for 15 weeks. RESULTS: Colon cancer incidence and mean number of tumors per rat at the end of the 15-week treatment period were significantly lower and smaller in the 5-aminosalicylic acid-treated group (10 percent and 0.2) than in the vehicle-treated (80 percent and 1.6) and untreated (68 percent and 1.1) control groups. However, the mean numbers of tumors per tumor-bearing rat were comparable: 1.5, 2, and 1.6. No distinct differences among the groups were observed in the tumor pathology with respect to their location (within 0-10 cm proximal to the anus), shape (plaque shaped or polypoid), size (<10 mm in diameter), invasion (restricted to the mucosa or submucosa), or histologic type (differentiated adenocarcinoma). CONCLUSION: Our results indicate that 5-aminosalicylic acid administered directly into the colonic lumen strongly suppresses the promotion stage of colon carcinogenesis.

Administration, Rectal↗

PubMed1986

Spontaneous and induced chromosomal aberrations and gene mutations in human lymphoblasts: mitomycin C, methylnitrosourea, and ethylnitrosourea.

The concentration-dependent mutagenic, clastogenic, and cytocidal activities of mitomycin C (MC), methylnitrosourea (MNU), and ethylnitrosourea (ENU) were measured in the human lymphoblast cell line TK6. For treatments resulting in fewer than 2 lethal hits, MNU, ENU, and MC gave rise to apparently linear dose-response curves for gene mutations (hgprt and tk genes) as well as for chromosomal aberrations. The numbers of induced mutants at the tk and hgprt loci were similar between the two loci for each compound. However, the ratio of mutagenic activity relative to the clastogenic activity (aberrations/cell) was lowest for mitomycin C, intermediate for methylnitrosourea, and highest for ethylnitrosourea. These results confirm in human cells the general observation that the processes of mutagenesis and clastogenesis are nonidentical: compounds vary independently in their mutagenic and clastogenic potentials.

Cell Line↗

PubMed2002

Synergistic tumor promoter effects of estrone and progesterone in methylnitrosourea-induced rat mammary cancer.

Tumor promoter effects of steroid hormones were tested in ovariectomized rats treated with the tumor initiator, methylnitrosourea. Continuous treatment with low doses of estrone induced tumor in 55% of experimental animals while intact control animals had a 96-100% incidence. Although progesterone alone produced no tumors in ovariectomized, methylnitrosourea-treated animals, estrone and progesterone acted synergistically, inducing tumorigenesis in 88% of treated rats. These results point to an important interaction between estrogens and progestins in promoting mammary tumorigenesis.

Alkylating Agents↗

PubMed2000

Prevention of N-methylnitrosourea-induced colon carcinogenesis in rats by oxygenated carotenoid capsanthin and capsanthin-rich paprika juice.

Epidemiological and animal studies have provided evidence that dietary carotenoids may reduce the risk of certain types of cancer. An inhibitory activity of oxygenated carotenoid capsanthin, a potent antioxidant, and paprika juice rich in capsanthin (3.54 mg/100 ml) against colon carcinogenesis was investigated in F344 rats. In Experiment I (short-term assay), six rats each were given a gavage of 5 mg, 0.2 mg, or 0.008 mg capsanthin six times a week for Weeks 2-6 after receiving three intrarectal doses of 4 mg N-methylnitrosourea in Week 1. The number of colonic aberrant crypt foci, preneoplastic lesions, at Week 6 was significantly fewer (by 42%) in the 0.2 mg capsanthin group, but not in other groups, than the control group. In Experiment II (long-term assay), five groups of 30 or 25 rats each received an intrarectal dose of 2 mg N-methylnitrosourea three times a week for Weeks 1-3, and had either of 10 p.p.m. or 2 p.p.m. capsanthin solutions, 1:2.5 and 1:16.7 diluted solution of paprika juice (containing 10 p.p.m. or 2 p.p.m. capsanthin), and tap water (control fluid) as drinking fluid throughout the experiment. The experimental groups were fed 0.2 mg or 0.04 mg capsanthin/day/rat. The colon cancer incidence at Week 30 was significantly lower in the highly diluted paprika juice group (40%), but not in the moderately diluted paprika juice group (60%) and the capsanthin solution groups (68% and 68%) than the control group (83%). The results suggested that paprika juice may affect colon carcinogenesis. However, capsanthin alone failed to inhibit colon tumorigenesis, in spite of suppression of aberrant crypt foci formation in the short-term assay. Further studies are needed to explain this discrepancy.

Animals↗

PubMed1980

Methylnitrosourea induction of thymomas in AKR mice requires one or two "hits" only.

Induction of thymomas by methylnitrosourea in many strains of mice requires 3 "hits". AKR mice develop thymomas spontaneously late in life, probably because of their large load of viral leukemia oncogenes. It was expected therefore, and so found, that methylnitrosourea induces thymomas in AKR mice with only 1 or 2 "hits". The viral oncogene therefore appears to function as a dominant "hit" gene cooperating with the chemical carcinogen.

AKR murine leukemia virus↗

PubMed1983

Reactions of methylnitrosourea, epichlorohydrin, styrene oxide and acetoxyacetylaminofluorene with polyamino acids.

Radioactive methylnitrosourea, epichlorohydrin, styrene oxide, and N-acetoxy-2-acetylaminofluorene were reacted with 14 different polyamino acids in vitro, to determine the relative reactivity of the functional groups in amino acids. All the carcinogens reacted preferentially with polycysteine and much less with polyhistidine. Reaction was also noted with polylysine, polymethionine and polyarginine, as well as with DNA. Epichlorohydrin and styrene oxide reacted also with polyserine. Methylnitrosourea and N-acetoxy-2-acetylamino-fluorene reacted relatively more with polyhistidine as compared with the epoxides. Polycysteine, polyhistidine and polylysine were more reactive towards styrene oxide at pH 8 than at pH 6.

2-Acetylaminofluorene↗

PubMed1994

Effects of inhibition of O6-alkylguanine-DNA alkyltransferase in rats on carcinogenesis by methylnitrosourea and ethylnitrosourea.

Many alkylating agents are potent carcinogens and there is considerable evidence that the formation of O6-alkylguanine in DNA can lead to mutations and the initiation of neoplastic growth. The repair of O6-methyl- or O6-ethylguanine in DNA is known to be brought about by the action of a protein termed O6-alkylguanine-DNA alkyltransferase. In order to investigate the role of this activity in the carcinogenic action of methylnitrosourea and ethylnitrosourea, O6-benzylguanine, a potent inhibitor of the alkyltransferase, was used. Groups of 20 female F344 rats were treated with the nitrosourea (0.2 mmol) by gavage in 10 weekly doses and a parallel group was also treated with 4 mg of O6-benzylguanine, 2 h prior to each dose of the nitrosourea. This dose of O6-benzylguanine was sufficient to reduce the alkyltransferase activity to zero in the liver for at least 8 h but activity had returned to about 60% of normal within 24 h. Animals were maintained until they became moribund, when they were killed, or until death related to tumors. The median week of death in the animals receiving methylnitrosourea was reduced from 60 wk to 52 wk by co-treatment with O6-benzylguanine. There was a smaller reduction from 55 to 50 wk in the rats receiving ethylnitrosourea. The treatment with O6-benzylguanine caused no significant change in the incidence of the principal tumors induced by the alkylnitrosoureas and there were no liver tumors produced by the combined treatments. These results show that the level of inactivation of alkyltransferase produced by this dose of O6-benzylguanine was not sufficient to greatly alter the potent carcinogenic effect of these doses of alkylnitrosoureas in this system.

Animals↗

PubMed1992

p53 mutations in C57BL/6J murine thymic lymphomas induced by gamma-irradiation and N-methylnitrosourea.

Genomic DNA from thymus tissue obtained from 47 C57BL/6J animals treated with the DNA alkylating agent N-methylnitrosourea or gamma-irradiation were screened for the presence of p53 mutations by using the single strand conformation polymorphism assay. Mutations were detected in 13% (4 of 30) of primary thymic lymphomas but none of 17 early stage lymphomas. The frequency of p53 mutations was the same in tumors induced by N-methylnitrosourea (2 of 15) or by gamma-irradiation (2 of 15). Mutations occurred in the highly conserved regions of the p53 gene in exons 5, 7, and 8. G:C to A:T transitions were commonly observed. One of 4 of the tumors analyzed contained two p53 mutations in exons 7 and 8. A previous study of the same tumors showed that ras mutations occurred with high frequency (greater than 50%) (E. W. Newcomb et al., Cancer Res., 48:5514-5521, 1988). Our data suggest that p53 mutations do not play a major role in carcinogen-induced thymic lymphomas studied here.

Animals↗

PubMed1983

Experiments on the influence of combined application of N-methylnitrosourea and 7,12-dimethylbenzanthracene in female Sprague-Dawley rats.

In a syncarcinogenesis experiment 144 female Sprague-Dawley rats were given combinations of 0, 5, 15 of 30 mg/kg methylnitrosourea intravenously and 0, 10, 30 of 60 mg/kg 7,12-dimethylbenzanthracene perorally. Despite identical organotropism of both compounds an increased carcinogenic effect was observed in the low dose range only where as the high doses of methylnitrosourea inhibited the manifestation of tumors after 7,12-dimethylbenzanthracene.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1982

Inhibition of development of methylnitrosourea-induced rat colonic tumors by peroral administration of indomethacin.

The nonsteroid antiinflammatory drug indomethacin, a prostaglandin synthesis inhibitor, inhibited the development of carcinogen-induced large bowel carcinomas in rats. CD-Fischer rats were given carcinogenic pretreatment with intrarectal instillation of 2 mg of methylnitrosourea 3 times a week from the 1st to the 5th week, in order to produce large bowel tumors. Thereafter, peroral administration of a high or low dose of indomethacin dissolved in drinking water (20 micrograms or 10 micrograms indomethacin/ml tap water) for 15 weeks was started at the 11th week, before the tumors developed. At autopsy in the 26th week just after the completion of the 15-week treatment, the incidence of developing large bowel tumors was significantly reduced in treated rats, compared to untreated control rats; 17% or 14% vs. 67%. However, at autopsy in the 36th week, 10 weeks after cessation of the treatment, the development of tumors in treated rats was significantly increased. Thus, indomethacin inhibited the development of methylnitrosourea-induced large bowel tumors in rats. The effectiveness of peroral administration of indomethacin was comparable to that of intraperitoneal administration. It is postulated that treatment with this drug may effectively prevent the development of large bowel cancer in patients at high risk.

Animals↗

PubMed2000

Effect of intragastric application of N-methylnitrosourea in p53 knockout mice.

Nullizygous p53 knockout (p53(-/-)) mice are highly susceptible to spontaneous tumorigenesis, in particular malignant lymphomas at an early age. Heterozygous p53 knockout (p53(+/-)) mice develop spontaneous tumors less frequently but may show increased susceptibility to chemical carcinogens. In this study, p53(-/-), p53(+/-), and p53 wild-type (p53(+/+)) mice were treated with N-methylnitrosourea (MNU) by gastric intubation (5 microg/g body weight) three times per week for 5 wk, starting at 5-6 wk of age. The surviving mice were killed when they were 56-57 wk old. All eight p53(-/-) mice treated with MNU developed malignant lymphomas with a shorter latent period (mean age = 16.4+/-0.5 wk) than their spontaneous tumors (61%, at age 23.3+/-1.4 wk). In p53(+/-) mice treated with MNU, malignant lymphomas developed at a higher frequency (eight of 27, 30%) than did spontaneous lymphomas (5%). Development of sarcomas in p53(-/-) and p53(+/-) mice was also significantly enhanced by treatment with MNU. All eight thymic lymphomas and three sarcomas in the p53(+/-) mice showed a loss of the remaining wild-type p53 allele. These results indicate that intragastric MNU treatment significantly enhanced spontaneous development of malignant lymphomas and sarcomas in both p53(-/-) and p53(+/-) mice. In the stomachs of 12 p53(+/-) mice, that were killed at the end of the experiment, two adenomas, one carcinoma in situ, and four adenocarcinomas were observed. In the stomachs of 31 p53(+/+) mice, eight adenomas and one carcinoma in situ were detected. The overall incidence of tumorous changes in the stomachs of p53(+/-) (seven of 12, 58%) and p53(+/+) (nine of 31, 29%) mice were not significantly different (P = 0.090). However, adenocarcinomas invading the submucosa were observed in p53(+/-) mice (four of 12, 33%) but not in p53(+/+) mice (zero of 31; P = 0. 004), suggesting a slightly higher susceptibility to gastric carcinogenesis induced by MNU in p53(+/-) mice. Mol. Carcinog. 28:97-101, 2000.

Adenocarcinoma↗