Biomedical subjects

R M Kovatch

Publications and source records attributed to R M Kovatch.

At least 37 records · Page 2Linked to original sources

PubMed1990

Ethylene dichloride: the influence of disulfiram or ethanol on oncogenicity, metabolism, and DNA covalent binding in rats.

Male and female Sprague-Dawley rats were exposed to 50 ppm ethylene dichloride (EDC) for 7 hr/day, 5 days/week, for 2 years by inhalation. Additional rats were exposed to 50 ppm EDC either with 0.05% disulfiram in the diet or with 5% ethanol in the drinking water. Histopathologic lesions related to the combination of inhaled EDC and dietary disulfiram were observed in the liver, mammary, and testicular tissues of rats. This combined exposure resulted in a significant increase in the incidence of intrahepatic bile duct cholangiomas in both male and female rats. Male rats exposed to both EDC and disulfiram also had an increased incidence of subcutaneous fibromas, neoplastic nodules, and interstitial cell tumors in the testes. The female rats exposed to EDC and disulfiram also had a higher incidence of mammary adenocarcinomas. No significant increase in the number of any tumor type was observed in rats exposed to only EDC, disulfiram, or ethanol. Similarly, no significant increase in the number of tumors was observed in rats exposed to inhaled EDC and ethanol in water. At the end of the 2-year period animals from each group were evaluated for EDC metabolism and DNA binding. Blood levels of EDC at the end of a 7-hr exposure period were significantly higher for rats exposed to both EDC and disulfiram than for rats exposed to EDC alone. In addition, the elimination of a single oral dose of radiolabeled EDC was affected. The urinary excretion of 14C from control rats was 47 to 55% of the administered dose with 28 to 30% detected as unchanged EDC in the breath. In disulfiram-treated rats, only 35 to 36% of the administered 14C was eliminated in the urine with 41 to 55% as unchanged EDC in the breath. The urinary metabolite HPLC profile was qualitatively unchanged by long-term EDC, disulfiram, or ethanol treatment, either alone or in combination, and consisted primarily of thiodiglycolic acid, thiodiglycolic acid sulfoxide, and chloroacetic acid.

Animals↗

PubMed1990

Neuropathological changes in transgenic mice carrying copies of a transcriptionally activated Mos protooncogene.

Independent transgenic mouse lines carrying the mouse Mos protooncogene linked to a retroviral transcriptional control sequence display behavioral abnormalities including circling, head tilting, and head bobbing. This dominant phenotype shows various degrees of penetrance in different transgenic founder animals and lines. Neuronal and axonal degeneration, gliosis, and inflammatory infiltrates are found in all transgenic mouse lines in which behavioral traits are present. Recordings of auditory-evoked potentials in mice of one of these lines demonstrate that transgenic mice are deaf; in these mice spiral ganglia degenerate and most of the cochlear hair cells are absent. By using an S1 nuclease protection assay, we have detected RNA expression of the transgene in all tissues examined and, in particular, at high levels in brain. In situ hybridization experiments show that Mos expression can be detected in specific areas of the central nervous system. Lesions are present in areas with demonstrable overexpression of Mos.

Animals↗

PubMed1989

Evaluation of the transplacental tumorigenicity of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in mice.

The transplacental tumorigenicity of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was assessed in three strains of mice: A/J; C3H/He x C57BL/6 F1 (hereafter called C3B6F1); and Swiss outbred [Cr:NIH(S)]. NNK (100 mg/kg) was administered i.p. on Days 14, 16, and 18 of gestation to A/J and C3H/He mice and on Days 15, 17 and 19 of gestation to the Swiss mice. The effects of postnatal treatment with tumor-promoting agents, including 0.05% sodium barbital in the drinking water until death or a single dose of Aroclor 1254 (a mixture of polychlorinated biphenyls, PCB) given on Postnatal Day 8 or 56, were also examined. Progeny were sacrificed at age 24 wk (A/J) or 72 wk (C3B6F1 and Swiss). Significant incidences of tumors occurred in the lungs of strain A/J progeny and in the livers of male C3B6F1 and Swiss progeny. Lung tumor incidence was 8 of 34 (24%) in the female offspring of the A/J mice treated with NNK, compared with 1 of 39 (3%) in controls (P less than 0.05). A 2-fold difference in lung tumor incidence in male offspring of NNK-treated (4 of 23, 13%) versus control (3 of 48, 6%) A/J mice was not of statistical significance. However, the incidence of lung tumors in NNK-exposed progeny A/J mice in both sexes combined (12 of 66, 18%) was also significantly greater than in controls (4 of 87, 5%). The incidence of liver tumors in the male C3B6F1 mice exposed transplacentally to NNK was 12 of 30 (40%) compared to 8 of 46 (17%) in controls (P less than 0.05). No effects of postnatal sodium barbital or PCB were observed on transplacental NNK tumorigenicity in C3B6F1 mice. The combined incidence of liver carcinoma in male mice in all NNK-treated groups (13 of 141, 9%) was significantly greater (P less than 0.05) than in controls (5 of 144, 3%). In male Swiss mice exposed transplacentally to NNK, the incidence of liver tumors was 3 of 57 (5%) compared to 0 of 35 controls, and postnatal treatment with PCB on Day 56 caused a significant increase (5 of 26, 19%) (P less than 0.05) in the incidence of NNK-induced liver tumors. The combined incidence of liver tumors in the male offspring of the Swiss mice treated with NNK, with or without PCB, was 8 of 83 (10%) which was significantly greater (P less than 0.05) than in controls (0 of 66).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1989

Modification of transplacental tumorigenesis by 3-methylcholanthrene in mice by genotype at the Ah locus and pretreatment with beta-naphthoflavone.

Transplacental lung and liver tumorigenesis in the mouse by 3-methylcholanthrene (MC) was assessed as a function of inducibility of MC metabolism in fetus and in mother, and of pretreatment of the mothers with a noncarcinogenic inducer, beta-naphthoflavone (beta NF). Pregnant (C57BL/6 X DBA/2)F1 females (genotype Ahb Ahd, inducer responsive) mated to DBA/2 males received 45 or 100 mg/kg MC on gestation day 17, and DBA/2 females (genotype Ahd Ahd, nonresponsive) mated to F1 males were given 5 or 30 mg MC/kg. These crosses generated both responsive and nonresponsive offspring. Phenotype and tumor incidences were determined at 13 months of age. The transplacental action of MC was dose dependent and resulted in more lung and liver tumors in induction-responsive offspring than in nonresponsive littermates in most comparisons. beta NF alone did not result in increased numbers of tumors. Significant, complex effects were seen when the mothers were pretreated with beta NF (150 mg/kg) on gestation day 15, before MC on day 17. The beta NF pretreatment protected the fetuses of the F1 mothers: there was a significant overall 30 to 50% reduction in numbers of lung and liver tumors. The greatest effect was seen in the induction-responsive males, who experienced a 50% reduction in both incidence and multiplicity of lung tumors after 100 mg MC/kg, compared with males exposed to MC only. By contrast, beta NF pretreatment of DBA mothers had no general effect but rather potentiated the action of the 5 mg MC/kg dose on multiplicity of lung tumors in inducible males, causing a significant 4-fold increase. It also caused a 60% increase in inducible male liver tumor multiplicity when given before the 30 mg MC/kg dose. Thus, beta NF pretreatment was protective when the mother was inducible, especially in the inducible fetuses of such a mother, but when the mother was noninducible the beta NF pretreatment had no effect in some situations and potentiated the action of the carcinogen in others, mainly in inducible fetuses. These results underscore the fact that induced maternal and fetal metabolism contribute to risk of transplacental tumorigenesis by MC in qualitatively opposite ways.

Animals↗

PubMed1989

Transplacental initiation of liver, lung, neurogenic, and connective tissue tumors by N-nitroso compounds in mice.

Epidemiological studies have implicated nitroso compounds as possible causative agents for human childhood cancers, including those of neurogenic origin. Published evidence from animal models, which is reviewed in this report, indicates that capacity for metabolic activation of nitrosamines is limited in rodent fetuses and that nitrosamines are correspondingly weak transplacental carcinogens. The C3H mouse fetus, however, has both moderate capability for activation of N-nitrosodimethylamine (NDMA) and proven susceptibility to transplacental causation of neurogenic tumors by a nitrosourea. We tested whether NDMA could act as a transplacental carcinogen in the C3H mouse, and whether it or N-nitrosodiethylamine (NDEA) would initiate neurogenic tumors. N-Nitrosoethylurea (NEU) served as positive control. C3H/HeNCr MTV- pregnant mice were treated ip on Gestation Day 16 or 19 with NDMA (0.1 mmol, 7.4 mg/kg, maximum nonfetotoxic dose), NDEA (0.5 mmol, 51 mg/kg), or NEU (0.4 mmol, 47 mg/kg). NDMA had significant transplacental carcinogenic effects, resulting in an increase in percentage female offspring with hepatocellular carcinomas and in average number of liver tumors after treatment on either gestational day, compared with controls. In the males there was a significant increase in numbers of liver tumors and carcinomas following Day 19 exposure. An increase in incidence of histiocytic and undifferentiated sarcomas was also of statistical significance. There was no change in number of pulmonary tumors. One intracranial schwannoma resulted. NDEA had no effect when given on Gestation Day 16, but caused a significant increase in liver and lung tumor numbers in both sexes when treatment was on Day 19. NEU induced the expected high incidence of lung tumors, significantly increased liver tumor incidence in females (Day 19 exposure), and produced schwannomas in 14 and 35% of the offspring after Days 16 or 19 treatment, respectively. The results show that NDMA at even a low dose had significant transplacental carcinogenic effects, including one schwannoma, which was most unlikely to have occurred spontaneously. However, this single neurogenic tumor contrasts with the absence of similar neoplasms in mice exposed transplacentally to NDEA, in view of the generally greater efficiency of ethylating agents as carcinogens for the nervous system in rodents. These data thus neither conclusively support nor refute the hypothesis that nitrosamines may initiate neurogenic tumors in fetuses.

Animals↗

PubMed1989

Experimental infection of cattle with Trypanosoma brucei rhodesiense.

Infection of cattle with various stocks of Trypanosoma brucei rhodesiense indicated that 49% developed a fatal CNS disease comparable to that found in man. Duration of disease ranged from 85 to 1613 days post infection. All eight stocks of T. b. rhodesiense tested, including those from Ethiopia and Tanzania, induced CNS disease. Blood became positive three to five days after inoculation, and after an initial peak of parasitaemia remained positive for three to five months. Subinoculation of blood into rodents subsequently became negative, although trypanosomes persisted in the lymph nodes for at least 56 to 1613 days. Only animals with CNS disease had detectable parasites in the CSF, usually after the animals had undergone severe deterioration. At post mortem examination trypanosomes could usually be found in the lymph nodes and CSF, and occasionally in the blood. Clinical signs included fever, hyperkinesia, weight loss, cerebellar ataxia, tremor, salivation and hyperaesthesia. A mild to moderate anaemia accompanied a transient thrombocytopenia and leucopenia. Animals subsequently developed leucocytosis. A pleocytosis and elevated total protein in the CSF was found, which persisted in some animals for long periods. Histopathological examination of the brain showed prominent generalized perivascular infiltrates consisting mainly of lymphocytes and plasma cells. Mott's cells were regularly observed. Vascular changes were characterized by swollen endothelium, infiltration of the vascular wall by inflammatory cells, and in some instances perivascular oedema. In the most severe cases evidence of ischaemia consisted of large numbers of astrocytes, rarefaction of the parenchyma, and areas of necrosis with loss of normal architecture. Demyelination was limited to perivascular areas. Occasionally a moderate to severe pancarditis was found.

Animals↗

PubMed1989

Cerebral trypanosomiasis in naturally-infected cattle in the Lambwe Valley, south Nyanza, Kenya.

Surveys in Zebu cattle in the Lambwe Valley in 1980 indicated that many (up to 70%) were infected with trypanosomes. The predominant parasite was Trypanosoma brucei sspl followed by T. congolense. Cerebrospinal fluid (CSF) analysis showed a high proportion of animals with pleocytosis and elevated total CSF protein. Trypanosomes were detected in CSF and signs of a central nervous system (CNS) disease were observed. Histopathological lesions in the CNS were identical to those found in experimentally-infected cattle and consisted of perivascular infiltrations, swollen endothelium of vessels, infiltration of the vascular wall, and perivascular oedema. The severest cases showed rarefaction, astrocytosis and areas of necrosis. Infected cattle transported to the Veterinary Research Laboratory were studied for up to four years. Absence of trypanosomes from the peripheral blood was common, and even subinoculation of lymph node aspirates and CSF were usually negative. Death was preceded by a period of weight loss and the development of severe CNS signs. An attempt to cure animals with Mel-B treatment failed. Serum from naturally-infected cattle neutralized T. b. rhodesiense stocks collected in the same area.

Animals↗

PubMed1989

Trypanosoma congolense: erythrocyte indices, plasma iron turnover and effects of treatment in infected cattle.

Early during the course of Trypanosoma congolense infection in cattle decreases in PCV occurred and coincided with increases in both MCV and MCH. The indices reached highest levels between eight and 12 weeks post-infection. By week 20 of infection MCV and MCH had decreased to pre-infection levels even though a substantial anemia persisted. Serum iron levels were elevated at eight weeks postinfection. (Infected 271 mg dl-1 v. control 140 mg dl-1) but decreased to low levels in infected animals by Week 28 (63 mg dl-1). At eight weeks post-infection PITR was elevated in infected animals (infected 2.6 mg dl-1 day-1 v. control 0.82 mg dl-1 day-1). By Week 28, however, PITR had fallen in infected animals to 0.62 mg dl-1 day-1 indicating a severe dyshaemopoesis since PCV levels averaged only 22%. Cattle which were treated with Berenil or that self-cured the infection had normal iron parameters when tested 61 weeks post-infection. Cattle treated early during the course of infection showed a significantly greater PCV response that those treated later during infection.

Anemia, Hemolytic↗

PubMed1989

Intraperitoneal mesotheliomas induced in mice by a polycyclic aromatic hydrocarbon.

Female mice of 6 strains (C3H/HeN, BALB/c, C57BL/6N, DBA/2, NIH Swiss, and AKR/N) were given the polycyclic aromatic hydrocarbon carcinogen 3-methylcholanthrene (MC) intragastrically in olive oil at a dose of 20 mg/kg, weekly for 12 wk. Half were pretreated 24 h before each MC administration with intraperitoneal beta-naphthoflavone (beta-NF, 150 mg/kg in olive oil), a noncarcinogenic inducer of certain cytochrome P-450 isozymes. Remaining mice were given olive oil prior to MC in the same fashion, or beta-NF in olive oil or olive oil alone without subsequent exposure to MC. All mice were killed when moribund or 13 mo after the start of treatment. Most of the mice, irrespective of treatment, exhibited signs of peritoneal injury, including inflammation, necrosis, granuloma formation, and mineralization. Mice of some of the strains also presented peritoneal mesotheliomas, in addition to a variety of other tumors. The incidence of unequivocal mesothelioma-bearing mice was 12/31 C3H/He and 9/32 BALB/c mice given only MC. Incidence was low in C57BL/6 (1/31) and DBA/2 (1/26), and no definite mesotheliomas were found in Swiss or AKR mice. There were in addition a number of cases of sarcoma (nine total in all strains) and of peritonitis (four total) that resembled mesothelioma to some degree and were initially diagnosed as much. beta-NF pretreatment reduced the frequency of mesotheliomas: there was only one definite mesothelioma in any of the beta-NF-MC groups, in a C3H/He mouse. Most of the mesotheliomas were mixed fibro-mesothelial type, sometimes with papillary epithelial excrescences. They typically grew in a botryoid pattern within the peritoneal cavity, coating the abdominal organs and sometimes actively invading these organs and the diaphragm. Some lesions exhibited pleomorphism, prominent giant cells, and frequent mitoses. In addition, several lesions consisting of severe mesothelial hyperplasia associated with tissue necrosis and inflammation were considered as possible early stages of mesothelioma development. It was postulated that peritoneal injury imposed by repeated intraperitoneal injection of oil acted as an enhancing factor for mesothelioma induction by MC. The pertinence of such a relationship to mechanisms in the etiology of human mesotheliomas is discussed.

Animals↗

PubMed1989

Carcinogenesis in rats by nitrosodialkylureas containing methyl and ethyl groups given by gavage and in drinking water.

The carcinogenic effects in male and female F344 rats of four nitrosodialkylureas containing methyl or ethyl groups have been compared by two modes of administration, gavage in oil solution or dissolved in drinking water. Weekly doses of 20 and 40 mumol were given to each rat by either route and treatment lasted usually 30 wk, resulting in a total dose per rat of 0.6 or 1.2 mmol. Nitrosodimethylurea and nitroso-1-methyl-3-ethylurea gave rise primarily to tumors of the nervous system, whereas nitrosodiethylurea and nitroso-1-ethyl-3-methylurea gave rise to tumors of the mammary gland, lung, intestinal tract, nervous system, and testicular mesotheliomas. The effect of nitrosodimethylurea was weaker than that of the other three compounds, as measured by rate of mortality with tumors. Drinking water treatment was less effective than treatment by gavage, by the same criterion. The tumorigenic effects paralleled those of the corresponding monoalkylnitrosourea, suggesting the presence in the target organs of receptors for which ethylnitrosoureas or methylnitrosoureas, respectively, have affinity.

Animals↗

PubMed1989

N-nitrosocimetidine as an initiator of murine skin tumors with associated H-ras oncogene activation.

N-Nitrosocimetidine (NCM) is a derivative of the drug cimetidine, a methylguanidine derivative used in the treatment of peptic ulcer, and is known to be inactive as a complete mouse skin carcinogen, even when given in repeated high doses for a long period. In the current experiment, NCM was tested for its ability to initiate skin tumors on Sencar mice. It was applied at doses of 1 or 0.3 mg, 5 times/week for 6 weeks, followed by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), 1 microgram, 2 times/week for 50 weeks. Controls received acetone. The higher NCM dose had significant effects on TPA-promotable tumors, resulting in shortened time to first tumor, increased incidence of all tumors (2-fold) and of malignant tumors (4-fold), and greater tumor growth rate (2-fold), compared with the acetone/TPA-treated mice. The mice given the lower NCM dose did not exhibit increased tumor incidence, but their tumors had a significantly higher growth rate (3-fold) than those of the TPA controls. NCM without TPA treatment caused no tumors. Thus, NCM is a definitive, though weak initiator of TPA-promotable tumors. Nine tumors from the NCM-treatment groups were analyzed for activated oncogenes by the NIH 3T3 cell transfection assay. Five were positive and four of these were found by selective oligonucleotide hybridization analysis to have an A to T transversion in the second position of codon 61 of the H-ras oncogene. One of two tumors from the acetone/TPA group also contained transforming DNA and demonstrated this mutation. None of the tumors had a G----A transition mutation at the second position of codon 12 of this oncogene. Tumor initiation by NCM may then be associated with the same oncogene mutation reported for mouse skin tumors initiated by other types of carcinogens, although occurrence of the mutated oncogene in TPA controls precludes a definitive conclusion.

Animals↗

PubMed1989

Comparative tumorigenicity of N-nitroso-2-hydroxymorpholine, N-nitrosodiethanolamine and N-nitrosomorpholine in A/J mice and F344 rats.

N-Nitroso-2-hydroxymorpholine (NHMOR), a genotoxic metabolite of the environmental carcinogens N-nitrosomorpholine (NMOR) and N-nitrosodiethanolamine (NDELA), was assayed for tumorigenicity in A/J mice and F344 rats. Groups of female mice were given NHMOR, NMOR or NDELA in the drinking water over a 10-week period; total doses were 53-55 mumol/mouse. The experiment was terminated after 30 weeks. Whereas NMOR was a potent tumorigen, inducing 20.3 lung tumors/mouse, NHMOR and NDELA were only weakly tumorigenic, giving 1.2 and 1.4 lung tumors/mouse respectively. Groups of female F344 rats were also given these three nitrosamines in drinking water for 50 weeks, as follows: NHMOR, total dose 0.6 mmol/rat; NHMOR, 1.2 mmol; NMOR, 1.1 mmol and NDELA, 5.6 mmol. The experiment was terminated after 120 weeks. NMOR was a potent carcinogen, inducing liver tumors in 100% of the rats. NDELA gave hepatocellular tumors in 70% of the rats. NHMOR was inactive even at the higher dose. The results of this study do not support the hypothesis that NHMOR is a proximate carcinogen of NDELA or NMOR.

Adenocarcinoma↗

PubMed1989

Chronic toxicity tests of sodium thiocyanate with sodium nitrite in F344 rats.

Sodium thiocyanate, a common environmental chemical, was found to increase the incidence of liver tumors in a group of rats treated with 0.08% in drinking water. To test the possibility that thiocyanate was catalyzing the formation of carcinogenic nitrosamines from amines and nitrite in the food, a group of 20 male and 20 female rats was given a higher dose of sodium thiocyanate (0.32%) together with sodium nitrite (0.2%) in drinking water. Similar groups of rats were given 0.32% sodium thiocyanate or 0.2% sodium nitrite in drinking water or were untreated. All treatments lasted most of the lifetime of the rats, at least 2 years. There was no difference between the groups, treated or untreated, in survival, or in the incidence of any tumor that could be related to the treatment. The results indicate that sodium thiocyanate is without carcinogenic activity in rats, alone or combined with sodium nitrite.

Animals↗

PubMed1989

Lack of effect of selenium on induction of tumors of esophagus and bladder in rats by two nitrosamines.

The effect of differences in level of dietary selenium on the induction of esophageal and bladder tumors in rats by two nitrosamines was investigated. Groups of 20 female F344 rats were given a synthetic diet containing less than 0.05 ppm Se to which selenium (as sodium selenite) was added at the concentration of 0.35, 0.7, 1.4 and 2.1 ppm selenium. These four groups, plus one without added Se, were treated with 20 ml per rat per day, 5 days a week, of a solution of nitrosomethylcyclohexylamine containing 5 mg/liter. A parallel five groups were treated in the same way with a solution of nitrosomethyl-3-carboxypropylamine in drinking water containing 600 mg per liter, as drinking water. Treatment lasted 28 weeks, at which time some animals had developed tumors. A group of 20 rats fed 0, 1.4 and 2.1 ppm Se was not treated with carcinogen. Rats consuming 1.4 ppm or 2.1 ppm Se gained weight more slowly than other groups. There was no significant difference in survival between the five groups treated with each carcinogen but receiving different dietary levels of selenium. Neither was there any significant difference between groups receiving each carcinogen in the incidence of tumors of the esophagus induced by nitrosomethylcyclohexylamine or of tumors of the urinary bladder induced by nitrosomethylcarboxypropylamine. Control rats on the synthetic diets did not survive as well as untreated rats eating regular chow diet. In these conditions there was no effect of dietary selenium levels on the induction of tumors in female rats by the two carcinogenic nitrosamines we used.

Animals↗

PubMed1989

Similar carcinogenic actions of nitrosoalkylureas of varying structure given to rats by gavage.

To relate the tumorigenic effects of directly acting alkylating nitrosoalkylureas to their chemical structure, a series of these compounds was given to F344 rats by gavage at approximately equimolar doses. In some cases, more than one dose rate was used. Potency, as measured by time to death with tumors, was similar for nitrosomethylurea and nitrosoethylurea, although the tumor pattern was different between the two. Nitrosoallylurea was of similar potency, and induced a spectrum of tumors similar to nitroethylurea. Nitroso-n-butyl-, n-amyl- and n-hexyl-ureas were less potent than nitrosoethylurea, but induced a similar pattern of tumors. All of the nitrosoureas induced tumors of the forestomach, usually in high incidence, except nitroso-2-hydroxypropylurea, which caused death of the rats with thymic lymphoma within 6 months. Nitroso-3-hydroxypropylurea was much less potent than its 2-isomer, but induced no tumors of the thymus and was the only one of this group to induce tumors of the glandular stomach. Only nitrosomethylurea induced a high incidence of tumors of the nervous system, but no mammary carcinomas, which most of the other nitrosoureas induced in high incidence in females. Tumors of the lung, duodenum, colon and intestines were induced by several of the compounds, more commonly in males than in females, but a high incidence of liver tumors was found only in rats of both sexes given nitroso-2-phenylethylurea.

Animals↗

PubMed1989

Carcinogenesis by nitrosamines and azoxyalkanes by different routes of administration to rats.

The effects of administering similar doses of some simple alkylating agents to rats by different regimens have been compared. Two of the compounds were methylating agents, nitrosodimethylamine and azoxymethane; two were ethylating agents, nitrosodiethylamine and azoxyethane; and nitrosomethylethylamine was both a methylating and an ethylating agent. The treatments gave rise to tumors in almost all treated rats. The results indicate the importance of pharmacokinetics in determining which organs are the targets of the alkylating carcinogens.

Administration, Intravesical↗

PubMed1989

The uniform carcinogenic action of alkylnitrosoureas in Syrian hamsters.

The carcinogenic effects of a number of alkylnitrosoureas in Syrian golden hamsters have been compared by administering them by gavage as solutions in corn oil/ethyl acetate. The compounds were methyl-, ethyl-, 2-hydroxyethyl-, 2-oxopropyl-, and 2-phenylethylnitrosourea and the dialkylnitrosoureas dimethyl- and diethylnitrosourea, ethylnitrosohydroxyethylurea, ethylnitroso-2-oxopropylurea, 2-oxopropylnitrosochloroethylurea, and hydroxyethylnitrosoethylurea. All were given at approximately equimolar doses and, in most cases, to male and female hamsters. Most of the hamsters died with tumors associated with the treatments. Methylnitrosourea, ethylnitrosourea, and hydroxyethylnitrosourea, but not oxopropylnitrosourea, gave rise to a high incidence of tumors of the forestomach, while the dialkylnitrosoureas produced smaller numbers of forestomach tumors. All of the alkylnitrosoureas induced hemangiosarcomas of the spleen, which was the most common tumor produced by these carcinogens. Tumors of other types were uncommon, except that ethylnitrosourea and ethylnitrosohydroxyethylurea induced tumors of the cervix in about half of the animals and ethylnitrosooxopropylurea induced some nervous system tumors. The small number of common target organs of alkylnitrosoureas in hamsters contrasted sharply with the broad spectrum of tumors they induced in rats, depending on the nature of the alkyl groups, and with a quite different order of potency in the latter species.

Animals↗

PubMed1988

Comparative carcinogenesis by nitrosomethylalkylamines in Syrian hamsters.

Six homologous nitrosomethyl-n-alkylamines, from n-propyl (C-3) to n-octyl (C-8), were administered by gavage to groups of 12 male and 12 female Syrian golden hamsters as solutions in corn oil:ethyl acetate (2:1). The solutions of C-8 to C-4 were equimolar; nitrosomethyl-n-butylamine (C-4) and nitrosomethyl-n-propylamine (C-3) were given at a lower concentration. Treatment with 0.2 ml of solution lasted 23 to 50 wk, being stopped when several hamsters had died. Additional groups of hamsters were treated similarly with nitrosomethylaniline and nitrosomethylcyclohexylamine. Excepting hamsters given the latter, treated animals had reduced survival compared with controls. The incidence of tumors in hamsters given nitrosomethylaniline and nitrosomethylcyclohexylamine was low and occurred in the liver, lungs, and spleen. Hamsters treated with nitrosomethyl-n-propylamine and nitrosomethyl-n-butylamine suffered the greatest decrease in survival. Potency judged by this criterion decreased as the size of the molecule increased in the homologous series. Virtually all of these treated hamsters died with tumors not seen in controls. These tumors, which were common in hamsters given all of the nitrosomethyl-n-alkylamines, were in the liver, lung, forestomach, and nasal mucosa, but the incidences varied somewhat between the compounds and between sexes. Bladder tumors were seen only in hamsters given nitrosamines containing even numbers of carbon atoms in the chain, namely, nitrosomethyl-n-hexylamine and nitrosomethyl-n-octylamine.

Animals↗