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At least 19 recordsLinked to original sources
PubMed1976

DNA repair synthesis in guinea pig pancreatic slices following in vitro exposure to N-nitrosomethylurethane.

The incorporation of thymidine into DNA in the presence of hydroxyurea (HU) by guinea pig pancreatic slices following exposure to N-nitrosomethylurethane (NMUT) was used to follow DNA repair synthesis. HU was used to suppress normal replicative DNA synthesis. Slices from the duodenal segment of the pancreas were exposed for periods of 15 to 90 min to NMUT at concentrations of 2 to 20 mM, then incubated in tritiated thymidine ([H3]-TdR) free of carcinogen, and radioactivity in DNA was determined. NMUT induced a a dose- and time-dependent increase in HU-insensitive thymidine incorporation. This stimulated incorporation, which could be attributed to repair synthesis, occurred immediately following the treatment and was largely complete within 3 h.

Animals↗
PubMed1980

Diabetogenic effect of N-nitrosomethylurea and N-nitrosomethylurethane in the adult rat.

Sodium nitrite and two N-nitroso compounds, N-nitrosomethylurea (NMU) and N-nitrosomethylurethane (NMUT) have been investigated in the adult rat with regard to their in vivo effects on glucose tolerance and insulin response to glucose. Their effects have been compared to the diabetogenic action of streptozotocin (SZ). Glucose challenge (0.5 g/kg) in order to test insulin secretion in vivo gives the same result in the sodium nitrite-treated (25 mg/day during 2 months administered in drinking water) as in the control rats. In the NMU-treated (100 mg/kg i.p.) and in the NMUT-treated (100 mg/kg i.p.) glucose-induced insulin secretion tested 1 or 8 days after drug administration is severely decreased during the second test, especially in the NMUT-treated rats. Rats receiving STZ (35 mg/kg i.v.) exhibit sluggish insulin secretion as soon as the first test. Since in situ formation of nitrites and nitrosamines has been detected in human, one wonders about their role in the aetiology of human diabetes.

Animals↗
PubMed1976

DNA repair synthesis in guineapig pancreas following exposure to nitrosomethylurethane.

NMUT, a known pancreatic carcinogen in guineapigs, alkylates pancreatic DNA and RNA, both in vivo and in vitro. Following the in vivo administration of a single maximum tolerated dose of NMUT (30 mg/kg), a significant increase in 3H-Tdr incorporation into DNA was observed in the duodenal segment of the pancreas after four days; this increase in thymidine incorporation probably represents in vivo DNA repair synthesis. The level of normal DNA synthesis was greater in the duodenal segment than elsewhere in the pancreas. In vitro exposure of pancreatic slices from the duodenal segment to 20 mM NMUT for 30 minutes resulted in a significant increase in 3H-TdR incorporation into DNA in the presence of HU, reflecting DNA repair synthesis following NMUT-induced DNA damage; normal DNA synthesis in the pancreatic slices in vitro was markedly suppressed by 10 mM HU. Studies on the kinetics of DNA repair synthesis in pancreatic slices indicated an initial increase of 3H-TdR incorporation, followed by a steady time-dependent decline. It appears that most of the DNA repair synthesis occurs within two hours after exposure to NMUT.

Animals↗
PubMed1982

Studies of a deuterium isotope effect in carcinogenesis by N-nitroso-N-alkylurethanes in rats.

Nitroso-N-methylurethane and nitroso-N-ethylurethane were administered to groups of 20 female F344 rats in corn oil solution by gavage. Each rat received once a week 0.2 ml of solution containing 7 mg/ml or 1.75 mg/ml of the methyl compound or 8 mg/ml or 2 mg/ml of the ethyl compound for 20 weeks. In parallel with these treatments additional groups of rats were given equimolar dose of nitrosomethylurethane and nitrosoethylurethane fully labeled with deuterium in the N-alkyl groups. All animals were allowed to die naturally. The total doses received by the rats were 0.2 mmol at the higher concentration and 0.05 mmol at the lower concentration. Almost all of the treated rats died with papillomas and carcinomas of the forestomach (non-glandular stomach), and the other induced tumors of significance were carcinomas and papillomas of the esophagus in rats given the 7 mg/ml dose of nitrosomethylurethane, both labeled and unlabeled. There was no significant difference in tumor incidence or rate of mortality from tumors that would indicate a difference in carcinogenic effectiveness between the nitrosoalkylurethanes and their deuterium-labeled counterparts. Apart from the esophageal tumors induced only by nitrosomethylurethane at the higher dose, there was no significant difference in carcinogenic effectiveness between the methyl and ethyl nitrosourethanes.

Animals↗
PubMed1979

Correlation of biochemical and morphological changes induced by chemical injury to the lung.

Comparison has been made of injury to the rat pulmonary alveolar parenchyma evoked by intravenous injection of N-nitrosomethylurethane, intratracheal instillation of 3-methylcholanthrene or repeated inhalation for up to 15 days of carbon tetrachloride, trichloroethylene or gasoline vapour. Biochemical analyses, including assessment of rates of RNA and DNA synthesis and secretion of pulmonary surfactant, were correlated with morphological changes determined by electron microscopy. Single doses of N-nitrosomethylurethane or 3-methylcholanthrene inhibited incorporation of [14C] orotate into lung RNA 1--3 days after treatment. Daily exposure for 30 min to carbon tetrachloride or trichloroethylene vapour caused less marked reduction in orotate incorporation. Ultrastructural examination revealed that 3-methylcholanthrene toxicity was characterised by cytoplasmic change including disruption of surfactant lamellaie of Type 2 pneumocytes and variable degenerative changes Type 1 pneumocytes. Eight to ten days after treatment, the morphological evidence of hypertrophy/hyperplasia and transformation of Type 2 pneumocytes correlated well with biochemical evidence of stimulated incorporation of [3H]thymidine. Inhalation of carbon tetrachloride or trichloroethylene vapour produced milder responses including occasional degenerative changes in Type 1 pneumocytes, reduced numbers of surfactant lamellae in Type 2 pneumocytes and no change in [3H]thymidine incorporation. In contrast to the gradation of injury produced by the various chemicals, all procedures caused a marked and reproducible reduction in secretion of pulmonary surfactant as determined by endobronchial lavage. Following solvent inhalation, reduced recovery of surfactant was detected within 5 days of repeated exposure and thereafter no further change in this depressed level resulted from continued exposure for a further 10 days. The data are discussed in terms of a generalised pattern of response by pulmonary alveolar tissue to chemical injury and the apparent sensitivity of surfactant secretion as an indicator of damage to the lung.

Animals↗
PubMed1983

Carcinogenesis by combinations of N-nitroso compounds in rats.

Five N-nitroso compounds were administered individually or in various combinations to groups of 20 female F344 rats to examine possible additive or synergistic effects on mortality rate and the induction of tumours. Combination of the oesophageal carcinogen dinitroso-2,6-dimethylpiperazine with nitrosodiethylamine, which also induces oesophageal tumours, or with nitrosoethylmethylamine, which induces liver tumours, did not appear to increase tumour incidence. Similarly, combination of nitrosodiethylamine with the bladder carcinogen nitrosomethyldodecylamine did not increase the formation of either bladder or oesophageal tumours compared with the effects of either compound alone, although an additive effect was suggested by a higher incidence of liver tumours after the combined treatment than after treatment with either compound alone. Nitrosomethylurethane, which induces tumours of the forestomach in rats, appeared to enhance the effectiveness of nitrosoethylmethylamine and dinitroso-2,6-dimethylpiperazine in inducing tumours of the oesophagus, and increased the rate of death. Nitrosomethylurethane given, at a somewhat higher dose, in combination with both of these compounds increased the incidence of oesophageal tumours even when the treatment lasted only 4 wk. This evidence suggests that additive or synergistic effects of combinations of N-nitroso compounds at low dose rates can be demonstrated in small groups of rats.

Animals↗
PubMed1976

Carcinogenesis in Sprague-Dawley rats of N-nitroso-N-alkylcarbamate esters.

Nitrosocarbaryl, nitroso-N-methylurethane and nitroso-N-ethylurethane were administered by gavage in olive oil solution to groups of 12 female Sprague-Dawley rats. The dose was 0.2 ml of 0.11 M solution once a week for 10 weeks, a total dose of 0.22 mmol. The rats given nitrosocarbaryl survived longer, but had as high an incidence of tumors (75%) as did rats given nitrosomethylurethane. Most of the tumors induced were invasive squamous carcinomas of the stomach. Nitrosoethylurethane appeared to be a little more potent than nitrosomethylurethane; all 12 animals in this group had squamous stomach tumors at death. A higher total dose of nitrosocarbaryl, 1.3 mmol, given to male rats twice weekly for 20 weeks did not produce a higher incidence of stomach tumors than did thelower dose in females, although the males died earlier with tumors.

Administration, Oral↗
PubMed1975

Pre- and postnatal toxicity induced in guinea pigs by N-nitrosomethylurea.

Oral administration of N-nitrosomethylurea at maximally tolerated doses to guinea pigs on alternate days from days 34-58 of pregnancy induced prenatal toxicity, as evidenced by a high frequency of stillbirths and intrauterine growth retardation, and postnatal toxicity, as evidenced by stunting and progressive mortality. Similar administration of N-nitrosomethylurethane at maximally tolerated doses did not induce such toxic effects.

Abnormalities, Drug-Induced↗
PubMed1982

Comparison of the carcinogenic effectiveness in mouse skin of methyl- and ethylnitrosourea, nitrosourethane and nitrosonitro-guanidine and the effect of deuterium labeling.

The carcinogenic activities of a number of directly acting methylating and ethylating agents have been compared by mouse skin painting in acetone solution. Nitrosomethylurethane and nitrosoethylurethane failed to induce tumors after greater than 60 weeks treatment. Nitrosomethylurea was somewhat more effective than nitrosoethylurea, as measured by the longer latent period than nitrosoethylurea, as measured Nitrosomethylnitroguanidine, by the same measure, was a weaker carcinogen than nitrosoethylnitroguanidine at both dose levels used (0.02 M and 0.008 M); the latter compound was the most potent skin carcinogen of those examined. There was no significant difference in carcinogenic effectiveness when the alkyl group of the nitrosoureas or the nitronitrosoguanidines contained deuterium instead of hydrogen, which supports the concept that alkylation of cellular macromolecules by the intact alkyl group is responsible for carcinogenesis by these compounds.

Administration, Topical↗
PubMed1970

Synergism between cysteine and alkylating agents.

Contrary to expectation, l-cysteine did not protect Escherichia coli from the lethal action of two monofunctional alkylating agents (nitrosomethylurethane and methylmethane sulfonate). The antibacterial action of these compounds was actually greatly enhanced by l-cysteine. This synergistic effect was also exhibited, to some extent, by d-cysteine but not by homocysteine, S-methylcysteine, or serine. The synergistic action between methylating agents and l-cysteine was not due to the formation of S-methylcysteine. l-Cysteine had no effect on the bacteriostatic action of ethylmethane sulfonate.

Alkanes↗
PubMed1975

A colon tumor model for anticancer agent evaluation.

Colon tumors of mice were induced with 1, 2-dimethylhydrazine, N-nitroso-N-methylurethane, methylnitrosourea, and 4-methyl-N'-nitro-N-nitrosoguanidine. Of 82 transplantation attempts, four were successful, and the four tumors have been maintained as distinct tumor lines by subcutaneous transplantation. The tumors graded from II, adenocarcinoma, to IV, undifferentiated carcinoma. Volume-doubling times varied over a three-fold range, and metastatic potential ranged from 5 to about 100%. The tumors responded to treatment with some of the same agents found to be active in man. These included cyclophosphamide, 5-fluorouracil, and certain nitrosoureas. Preliminary evidence suggests that these tumor lines may be useful as experimental models.

Animals↗
PubMed2005

Dosing and scheduling influence the antitumor efficacy of a phosphinic peptide inhibitor of matrix metalloproteinases.

The in vivo disposition and antitumor efficacy of a newly developed phosphinic matrix metalloproteinase inhibitor (RXP03) were examined. RXP03 potently inhibits MMP-11, MMP-8 and MMP-13, but not MMP-1 and MMP-7. Twenty-four hours after i.p. injection into mice, most of the RXP03 was recovered intact in plasma, feces (biliary excretion) and tumor tissue. Pharmacokinetic parameters indicated that, after an i.p. dose of 100 microg/day, the plasma concentration of RXP03 over 24 hr remained higher than the Ki values determined for MMP-11, MMP-8 and MMP-13. Efficacy of RXP03 on the growth of primary tumors induced by s.c. injection of C(26) colon carcinoma cells in mice was observed to depend both on RXP03 doses and treatment schedules. Tumor volumes in mice treated for 18 days with 50, 100 and 150 microg/day of RXP03 were decreased compared with control tumor volumes, 100 microg/day being the most effective dose. Treatment at higher dose (600 microg/day) did not significantly reduce the tumor size as compared to control. Short treatments with RXP03 100 microg/day, 3 to 7 days after C(26) inoculation, were more effective on tumor growth than continuous treatment over 18 days. Strikingly, RXP03 treatment started 6 days after the C(26) injection and continued until day 18 led to stimulation of tumor growth, as compared to control. These paradoxical effects, depending on the RXP03 treatment schedule, underline the need to define carefully the spatiotemporal function of each MMP at various stages of tumor growth to achieve optimal therapeutic effects by MMP inhibitor treatment.

Alkylating Agents↗
PubMed1975

Chemical carcinogenesis and the pancreas.

Although carcinoma of the pancreas is an increasingly prevalent form of human cancer, there has been relatively little experimental work on the etiology of this tumor until recently, probably because of the lack of adequate experimental models. However, at least two good experimental systems are now available. Several epidemiologic investigations suggest that chemical carcinogens may induce cancer of the pancreas in humans. If this is so, chemicals must reach the pancreas either through the blood supply or by reflux into the pancreatic duct from bile or duodenal contents. The route of exposure may vary according to the chemical and physical characteristics of different chemical carcinogens. Additional work is needed to determine the ability of different classes of chemicals to reach the pancreatic duct by these routes and the presence of enzymes required for activation of carcinogens in the pancreas. Levels of such enzymes as well as the response of cells of the pancreatic duct to carcinogens may be affected by the physiologic state of the pancreas or pathologic conditions within it. Research is needed to investigate these possibilities.

4-Hydroxyaminoquinoline-1-oxide↗
PubMedDate not supplied

Cardiopulmonary function of cats with respiratory distress induced by N-nitroso N-methylurethane.

The purposes of this study were to determine the effects of positive end-expiratory pressure (PEEP) and end-expiratory lung volume on systemic blood flow, whether PEEP levels yielding maximum systemic oxygen transport are associated with maximum lung compliance, and the effects of end-expiratory lung volume on pulmonary resistance to gas flow, in an animal model of respiratory distress. Twelve cats were inoculated with 12 mg/kg N-Nitroso N-Methylurethane (NNNMU) to induce respiratory distress. The NNNMU caused a 76% decrease in disaturated phosphatidyl-choline of lung lavage, a 34% decrease in functional residual capacity (FRC), an 80% decrease in lung compliance, an 88% increase in pulmonary resistance to gas flow, a 43% decrease in PaO2, and a 37% decrease in oxygen consumption. Systemic blood flow and systemic oxygen transport were not significantly altered by the chemically induced respiratory distress. PEEP levels of 5.1 +/- 0.8 cm H2O returned end-expiratory lung volume to normal FRC levels. Increases in PEEP caused systemic blood flow to decrease even when end-expiratory lung volume was below or equal to normal FRC levels but did not significantly affect systemic oxygen transport, lung compliance, or pulmonary resistance. We conclude that in cats with NNNMU-induced respiratory distress: PEEP causes decreases in systemic blood flow, lung compliance and systemic oxygen transport are not clear indicators of optimal PEEP level, and returning end-expiratory lung volume to normal FRC does not significantly reduce pulmonary resistance to gas flow.

Airway Resistance↗