Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of ras gene activation in the development of lung tumors induced by N-ethyl-N-nitrosourea (ENU) and N-nitrosodiethylamine (DEN) was evaluated in the A/J mouse, a strain susceptible to chemically induced lung tumors. DNAs isolated from both ENU- and DEN-induced lung tumors were screened for activating mutations in the K-ras gene by utilizing the polymerase chain reaction (PCR) and direct sequence analysis. Mutations in the K-ras gene were detected in 11 of 11 ENU-induced tumors and 23 of 28 DEN-induced tumors. In ENU-induced tumors, there were three GC----AT transitions in the second base of codon 12, and seven AT----GC transitions and one AT----TA transversion in the second base of codon 61. A similar spectrum of K-ras mutations was observed in DEN-induced lung tumors: five GC----AT transitions and two GC----TA transversions in the second base of codon 12, and sixteen AT----GC transitions at the second base of codon 61. Ninety-one percent (31/34) of the observed mutations are consistent with the formation of the promutagenic O4-ethylthymine and O6-ethylguanine adducts in DNA. Therefore, lung tumors from the A/J mouse induced by DEN and ENU could be initiated by the interaction of reactive metabolites with specific sites in the K-ras gene. This is the first clear example of activation of the K-ras gene by ethylating agents in a rodent lung tumor system.
Carcinogenesis 1992 Sep
PMID:Mutagenesis of the K-ras protooncogene in mouse lung tumors induced by N-ethyl-N-nitrosourea or N-nitrosodiethylamine. 139 43

The present report describes a study of the hepatocarcinogenic potential of a second large assay series of 94 compounds carried out using the rapid bioassay system (DEN-PH model) developed in this laboratory and based on the two-step concept of hepatocarcinogenesis. Male F344 rats were initially given a single dose of diethylnitrosamine (DEN, 200 mg/kg body weight ip) and, starting 2 wk later, were treated with test compounds for 6 wk and then killed, all rats being subjected to a two-thirds partial hepatectomy at wk 3. Carcinogenic potential was scored by comparing the numbers (no./cm2) and areas (mm2/cm2) of induced glutathione S-transferase placental form (GST-P) positive foci in the livers of groups of about 15 rats with those of corresponding control groups given DEN alone. Positive was scored for a significant increase (P < 0.05) in quantitative values of GST-P positive foci, negative for no change or a decrease. Results for the 94 compounds were also compared with previously published data from Salmonella/microsome (Ames) tests and long-term carcinogenicity studies in rats and mice. Of the known liver carcinogens, 14 out of 14 (100%) mutagenic (Ames test) compounds and 10 out of 12 (83%) non-mutagenic compounds gave positive results in our DEN-PH system (mean 92%). Two hepatocarcinogenic peroxisome proliferators did not enhance the development of GST-P positive foci. Carcinogens other than hepatocarcinogens gave fewer positive results (five out of 17, 29%). One of the 13 compounds reported as non-carcinogenic, malathion, gave positive results in the DEN-PH assay, suggesting that this compound is a weak hepatocarcinogen or tumour promoter for hepatocarcinogenesis based on the two-stage hypothesis for carcinogenesis. The present study also provided information regarding the inhibitory potential of nine compounds. The practical usefulness and benefits of the DEN-PH protocol for the rapid screening of carcinogenic agents are discussed.
 ...
PMID:Liver medium-term bioassay in rats for screening of carcinogens and modifying factors in hepatocarcinogenesis. 147 91

As part of an evaluation of the effectiveness of using ras mutation analysis for distinguishing carcinogen-induced from spontaneous tumors, we examined the profile of ras gene point mutations in spontaneous, 7,12-dimethylbenz[a]anthracene (DMBA)-induced, and N-nitrosodiethylamine (DEN)-induced lung tumors from Crl:CD-1(ICR)BR (CD-1) mice. Although all of the lung tumors were assayed for mutations in the Ha-ras, Ki-ras, and N-ras genes (codons 12, 13, and 61), only Ki-ras mutations were found, which is consistent with other studies that have noted a strong preference for Ki-ras gene activation in mouse, rat, and human lung tumors. We found that spontaneous CD-1 mouse lung tumors had a very high frequency of Ki-ras gene activation (17 of 20 tumors; 85%), distributed among codons 12 (5 of 20), 13 (1 of 20), and 61 (11 of 20). DMBA-induced lung tumors had a slightly higher frequency of Ki-ras gene mutations (16 of 16; 100%), again distributed among codons 12 (5 of 16), 13 (2 of 16), and 61 (9 of 16). However, seven of the DMBA tumors had mutations qualitatively different from those found in spontaneous tumors. In contrast to DMBA-induced tumors, DEN-induced tumors had a lower frequency of Ki-ras mutations (36%) when compared with spontaneous lung tumors, suggesting that DEN primarily induces lung carcinogenesis by a mechanism other than ras gene activation. Thus, although spontaneous and induced CD-1 mouse lung tumors have a strong tissue-specific preference for carrying an activated Ki-ras gene, the nature of the initiating carcinogen can influence the frequency or profile of Ki-ras mutations.
 ...
PMID:Activation of the Ki-ras gene in spontaneous and chemically induced lung tumors in CD-1 mice. 150 45

Inactivating point mutations and small deletions in the p53 tumor suppressor gene have been found in human liver and lung tumor--derived cell lines and tumors. However, little evidence has been reported concerning inactivation or mutation of the p53 gene in mouse primary tumors. To examine CD-1 mouse liver and lung tumors for mutations in the p53 gene, we first sequenced p53 introns 5-8 so that polymerase chain reaction amplification and sequencing primers located within the introns could be prepared. Use of these primers prevented amplification of the mouse p53 pseudogene and allowed sequencing of exons 5-8 in their entirety as well as their intron-exon junctions. DNA isolated from CD-1 mouse tumors was amplified and directly sequenced using nested primers. Nine spontaneous hepatocellular carcinomas (HCCs) and 34 chemically induced HCCs (induced by single intraperitoneal injections of N-nitrosodiethylamine [DEN] [8 HCCs], 7,12-dimethylbenz[a]anthracene [DMBA] [8 HCCs], 4-aminoazobenzene [8 HCCs], and N-OH-2-acetylaminofluorene [10 HCCs]) were examined for mutations in exons 5-8 of the p53 gene. In addition, 12 spontaneous, 10 DMBA-induced, and 13 DEN-induced lung adenocarcinomas or adenomas were analyzed for mutations. No mutations were found in any of the tumors examined. However, a mutation was demonstrated at codon 135 in the positive-control plasmid LTRp53cG(val). The results of this study suggest that inactivation of p53 is unlikely to play a major role in murine lung or liver carcinogenesis. However, inactivation of p53 may occur at a very low frequency, or it may occur as a late event and therefore be present in only a very small number of the tumor cells, rendering it undetectable by this method. Lastly, although few p53-inactivating mutations are found outside of exons 5-8 in human tumors, it is possible that these murine tumors contained mutations outside of this region and were therefore missed by our approach.
 ...
PMID:Murine p53 intron sequences 5-8 and their use in polymerase chain reaction/direct sequencing analysis of p53 mutations in CD-1 mouse liver and lung tumors. 154 44

In order to elucidate whether T-2 toxin (T-2) and nivalenol (NIV), the naturally occurring trichothecene mycotoxins in food and feed, are carcinogenic or possess an ability to modulate aflatoxin B1 (AFB1)-induced hepatocarcinogenicity, a medium-term liver bioassay was carried out. F344 male rats were given a single i.p. injection of diethylnitrosamine (DEN, 200 mg/kg), and then fed the test trichothecenes in diet (2 and 5 p.p.m. T-2 or 6 p.p.m. NIV) for 6 weeks beginning 2 weeks after the injection. Some control groups received DEN alone. For synergism between AFB1 and the trichothecenes, DEN-initiated rats as above were given a single i.p. injection of AFB1 (0.5 mg/kg) 2 weeks later and were fed a NIV-containing diet (6 p.p.m.) for 6 weeks. The other control group received the vehicle alone. Control rats not initiated with DEN were also treated with AFB1, NIV or T-2 alone as above. All rats were subjected to a two-thirds partial hepatectomy (PH) at week 3 and killed at week 8, and liver sections were analyzed by glutathione S-transferase placental form (GST-P) expression. In rats that did not receive DEN, AFB1 alone enhanced both the numbers and areas of GST-P-positive foci as reported earlier, while NIV or T-2 alone induced no marked changes. In rats initiated with DEN, AFB1 caused a marked expression of GST-P, and thus the hepatocarcinogenicity of AFB1 was reconfirmed. The expression of GST-P foci in rats fed T-2 or NIV was found to be at background level, indicating that the hepatocarcinogenicity was not predicted for the trichothecene mycotoxins such as T-2 and NIV by this medium-term bioassay system. In the group initiated by DEN followed by AFB1, on the other hand, an elevation of both the numbers and areas of GST-P-positive foci was observed by the subsequent feeding of rats with NIV, and this elevation was statistically significant from the sum totals of individual data of AFB1 or NIV alone. From this evidence, it is predicted that NIV causes an enhancing effect on AFB1-induced hepatocarcinogenesis.
Carcinogenesis 1992 May
PMID:Enhancement of GST-P-positive liver cell foci development by nivalenol, a trichothecene mycotoxin. 158 91

A multiple organ carcinogenesis model was used in male F344 rats to test the carcinogenic potential of (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo- 7H-pyrido[1,2,3-de][1,4] benzoxazine-6-carboxylic acid hemihydrate (levofloxacin, DR-3355, CAS 10086-85-4). After sequential treatment with diethylnitrosamine (DEN: carcinogen for the liver), N-methylnitrosourea (MNU: carcinogen for the esophagus, forestomach and thyroid) and dihydroxy-di-N-propylnitrosamine (DHPN: carcinogen for the lungs, kidney and urinary bladder), rats were treated with DR-3355, N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), catechol (CC) or phenobarbital (PB) to examine whether these compounds modified the carcinogenesis in multiple organs. As a result of histopathological examinations at study week 20, DR-3355 did not induce neoplastic lesions, nor did it enhance the occurrences of proliferative preneoplastic lesions. In contrast, BBN increased the incidences of hyperplasias and papillomas of the urinary bladder. CC enhanced the occurrences of hyperplasias and papillomas of the forestomach as well as submucosal glandular growth for the glandular stomach. PB increased the number of altered cell foci in the liver and the incidence of follicular cysts and hyperplasias of the thyroid. These results indicate that DR-3355 is not capable of promoting the development of tumors in rat multiple organs.
 ...
PMID:Effect of the new quinolone antibacterial agent levofloxacin on multiple organ carcinogenesis initiated with wide-spectrum carcinogens in rats. 162 38

Hepatocellular tumors were induced in 15 day old male B6C3F1 mice following a single exposure to N-nitrosodiethylamine (DEN; 5 mg/kg, i.p.). Tumors were collected at 38 and 65 weeks to compare the frequencies and types of mutations in the 61st codon of the H-ras oncogene. The 61st codon was amplified using the polymerase chain reaction (PCR). Allele-specific oligonucleotide (ASO) probes were used to determine the frequency and types of mutations present in these tumors. Forty-nine nodular hepatic lesions were obtained from seven animals at the 38 week timepoint. Five of these samples (10%) had mutations at the 61st codon with one CAA-AAA, one CAA-CGA and three CAA-CTA. Thirty-six nodular hepatic lesions were obtained from six animals at the 65 week timepoint. Ten of these samples (28%) had mutations at the 61st codon with one CAA-AAA, five CAA-CGA and four CAA-CTA. These data indicate that DEN-induced mutations at the 61st codon of the mouse H-ras oncogene (i) are an infrequent event, (ii) have different frequencies at the 38 and 65 week timepoints and (iii) are different from the types of mutations seen in spontaneous lesions.
Carcinogenesis 1992 Jul
PMID:Temporal changes in the mutant frequency and mutation spectra of the 61st codon of the H-ras oncogene following exposure of B6C3F1 mice to N-nitrosodiethylamine (DEN). 163 98

Spongiosis hepatis (SH), first reported as a distinct lesion associated with certain forms of hepatic neoplasia in rats, has also been induced with chemicals, in a predictable fashion, in small teleost fishes being studied as carcinogenesis research models. The sheepshead minnow (Cyprinodon variegatus), exposed to N-nitrosodiethylamine (DENA) in sea water, provided the model for this study. The fish developed SH and presented a spectrum of developmental or progressive stages of the lesion over a 140 week holding period following a 6 week exposure to / 57 mg/L DENA. The origin of SH in the fish model is homologous to that in the rat model, both species having the perisinusoidal cell (stellate cells of Ito) in the space of Disse as the cell of origin. Light (LM) and electron microscopy (EM) studies characterized the different pathogenetic stages of SH in liver of the sheepshead minnow and revealed a possible late transition of SH to putative polymorphic cell neoplasms. The possible preneoplastic or neoplastic nature of SH from its time of origin in chemically exposed fish to time of appearance of associated presumptive neoplasms is discussed. SH may be a bioindicator of exposure to certain chemicals in some vertebrate species, from fishes to mammals.
 ...
PMID:Spongiosis hepatis: chemical induction, pathogenesis, and possible neoplastic fate in a teleost fish model. 178 Jun 41

Dose-dependent modifying effects of quinacrine on induction of preneoplastic liver cell foci were investigated in male F344 rats. Six week old animals were injected i.p. with N-nitrosodiethylamine (DEN) at a dose of 200 mg/kg, and starting 2 weeks later, rats were given quinacrine at dietary levels of 20, 100 and 500 p.p.m. for 6 weeks. Groups without either DEN or quinacrine treatment were used as controls. At week 3 following DEN administration, all animals were subjected to two-thirds partial hepatectomy, and after killing the animals at week 8, development of preneoplastic liver cell foci was investigated using the glutathione S-transferase placental form (GST-P) as a marker. The numbers and unit areas of GST-P-positive foci per cm2 were significantly increased in the DEN/quinacrine (500 p.p.m.) group as compared to DEN-alone group values. An increase in number was also evident in the 100 p.p.m. but not the 20 p.p.m. treated group, no lesions being induced by quinacrine alone (500 p.p.m.). Electron microscopic study confirmed that quinacrine dose-dependently induces lipidosis in hepatocytes, i.e. markedly myeloid lamellar cytoplasmic inclusion bodies were observed. The results thus demonstrated that quinacrine treatment enhances GST-P-positive liver cell foci development in a dose-dependent way, this effect presumably being related to the induction of lipidosis.
Carcinogenesis 1991 Oct
PMID:Dose-dependent enhancing effects of quinacrine on induction of preneoplastic glutathione S-transferase placental form positive liver cell foci in male F344 rats. 193 72

Chenodeoxycholic acid (CDC), a dihydroxylated primary bile acid, was evaluated for promotional activity in the liver of rats using a two-stage initiation-promotion model. CDC is a primary bile acid that can attain high concentrations in serum and liver during induced or naturally occurring hepatocellular disorders. Female Sprague-Dawley rats were injected once (i.p.) with diethylnitrosamine (DEN, 150 mg/kg) or sterile physiologic saline (SAL, 0.85% NaCl). Two weeks later, rats in each group were placed into one of two subgroups and fed either NIH-31 mash (Control) or NIH-31 mash containing 0.5% CDC for a 10 week period. At the end of the feeding period, blood and liver samples were collected for determination of bile acid profiles and quantitation of hepatocellular foci respectively. Serum samples were analyzed for concentrations of individual bile acids using a HPLC method that utilizes a post-column enzymatic reaction and fluorescence detection. Liver slices from the left hepatic lobe were stained for foci positive for placental glutathione S-transferase. In serum, significant increases occurred in concentrations of all forms of CDC and were accompanied by mild, insignificant increases in lithocholic acid. Decreased serum concentrations occurred in all forms of cholic and deoxycholic acids. Analysis of liver sections revealed that rats treated with DEN-CDC had significant increases in numbers and volume of foci compared to those treated with DEN-Control. For rats in groups DEN-CDC and DEN-Control, the numbers of foci per square centimeter were 32 and 12; per cubic centimeter, 2221 and 937; and the per cent volume of foci, 1.487 and 0.385 respectively. In this study, CDC was a promoter of hepatocellular foci. Because concentrations of CDC in liver and serum increase in a variety of hepatobiliary disorders, the possibility that increases in endogenous concentrations can enhance the formation of hepatocellular foci is being explored.
Carcinogenesis 1991 Jan
PMID:Promotion of hepatocellular foci in female rats by chenodeoxycholic acid. 198 83


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>