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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiological studies have shown that inhalation of radon is associated with an increased risk for bronchogenic carcinoma in uranium miners. These alpha-emitting radon daughters also represent the largest component of background radiation to the general public. In the present study, the oncogenic transforming effects of single versus multiple doses of radon-simulated alpha-particles were examined using human papillomavirus-immortalized human bronchial epithelial cells. Endpoints such as growth kinetics, resistance to serum and 12-O-tetradecanoylphorbol-13-acetate-induced terminal differentiation, anchorage-independent growth and tumorigenicity in nude mice were used to assess the various stages of transformation in the bronchial epithelial cells. We show here, for the first time, that immortalized human cells in culture can be malignantly transformed by a single 30 cGy dose of alpha-particles. Transformed cells produced progressively growing subcutaneous tumors upon inoculation into athymic nude mice. Immunofluorescent staining of keratin and isozyme analysis of the cell lines subsequently generated from these tumors indicated that the cells were of human epithelial origin. Analysis of genomic DNA from the tumorigenic cell lines using PCR amplification and restriction enzyme analysis demonstrated no point mutation at either codon 12/13 or 61 in any of the ras oncogenes examined (K-, N- and H-ras). This system provides an opportunity to study the cellular and molecular changes at the various stages in radiation carcinogenesis involving human cells.
Carcinogenesis 1994 Mar
PMID:Malignant transformation of human bronchial epithelial cells by radon-simulated alpha-particles. 811 24

To study the oncogenesis of human esophageal carcinoma, the expression of a variety of oncogenes was studied in 10 esophageal carcinoma cell lines and 16 pairs of tumor and nontumor tissues removed from patients with esophageal carcinoma. Northern blot analyses using 11 different oncogene probes revealed that 5 oncogenes, i.e. c-myc, c-H-ras, c-sis, c-raf, and c-fos, were expressed. Among them, a variant c-sis mRNA transcript of 2.7 kilobase (kb) was expressed in 7 of 10 cell lines and in 9 of 16 tumor tissues. Furthermore, an overexpression and an amplification of c-myc gene was observed in some cell lines. These results suggest that multiple oncogene expression may be required for the induction, maintenance, and progression of esophageal carcinoma. The expression of a 2.7-kb transcript, of c-sis and overexpression of c-myc gene may play some role in the carcinogenesis of esophageal carcinoma.
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PMID:Expression of multiple oncogenes in human esophageal carcinomas. 813 Nov 4

Morphologic transformation and tumorigenicity are separate cellular phenotypes in transformed 10T1/2 cells. We have investigated the levels of expression of genes for c-myc, c-H-ras, c-K-ras, c-N-ras, TGF beta and Rb in 42 morphologically transformed 10T1/2 cell lines, in an attempt to define the molecular mechanisms governing morphologic transformation and tumorigenicity in the 10T1/2 cell system. The 10T1/2 cell lines investigated generally overexpressed mRNAs for c-myc, c-H-ras, and TGF beta relative to the levels expressed by wild-type 10T1/2 cells (levels of expression > 1.5-fold that of wild-type 10T1/2 cells). In contrast, only half of these cell lines overexpressed mRNAs for c-N-ras and/or Rb relative to wild-type 10T1/2 cells, and only 25% overexpressed c-K-ras mRNA. The mean levels of mRNA expression for each of c-K-ras, c-N-ras and TGF beta genes in tumorigenic cell lines were significantly greater than the mean levels of expression in non-tumorigenic cell lines, suggesting an association between tumorigenicity and the levels of expression of these specific genes. In contrast, levels of expression for c-myc, c-H-ras and Rb genes were not correlated with tumorigenicity. Cell lines that coexpressed high levels of c-K-ras, c-N-ras and TGF beta genes were likely to be tumorigenic (11/12 cell lines were tumorigenic), whereas cell lines that coexpressed low levels of these genes were unlikely to be tumorigenic (1/10 cell lines were tumorigenic). High expression of TGF beta was sufficient for tumorigenicity in the absence of high levels of expression of c-K-ras and c-N-ras (5/5 cell lines were tumorigenic). Elevated expression of either c-K-ras or c-N-ras alone was insufficient for tumorigenicity, however, coordinate overexpression of both c-K-ras and c-N-ras was associated with tumorigenicity irrespective of the expression status for TGF beta (13/15 cell lines were tumorigenic). These results suggest that overexpression of c-myc, c-H-ras and TGF beta are commonly associated with, and possibly mechanistically related to, the process of morphologic transformation in 10T1/2 cells. In addition, these results suggest that progression from morphologic transformation to tumorigenicity in 10T1/2 cell lines is frequently accompanied by overexpression of c-K-ras and c-N-ras, and by enhancement of the level of overexpression of TGF beta.
Carcinogenesis 1994 May
PMID:Overexpression of c-K-ras, c-N-ras and transforming growth factor beta co-segregate with tumorigenicity in morphologically transformed C3H 10T1/2 cell lines. 820 61

Oxazepam has been the subject of recent toxicological and carcinogenesis studies because it is a commonly prescribed tranquilizer and has been shown to cause tumors in rodents. In this study, male and female B6C3F1 mice received 0, 125, 2500 or 5000 p.p.m. oxazepam in the diet for up to 2 years. Hepatocellular adenomas and carcinomas, as well as hepatoblastomas, which developed in these mice, were examined for the presence of activated ras proto-oncogenes. DNA was isolated from 20 or more tumors from each exposure group and analyzed by oligonucleotide hybridization, single-stranded conformation polymorphism analysis and direct sequencing of PCR-amplified H-ras gene fragments for codon 61 mutations. Thirteen of 37 (35%) hepatocellular adenomas and carcinomas from the 125 p.p.m. exposure group had mutations in codon 61, while mutations were detected in only 2 of 25 or 8% of the liver tumors from the 2500 p.p.m. exposure group and none of the 22 tumors from the 5000 p.p.m. group. This compares to 63% of 126 historical control liver tumors and 55% of 20 liver tumors from unexposed B6C3F1 mice in this study. In addition, 12 hepatoblastomas from the two high dose groups were examined for H-ras mutations at codon 61, but none were detected. No tumor DNAs from any of the exposure groups tested had mutations in codons 12, 13 or 117 of the H-ras gene or codons 12 or 13 of the K-ras gene, the other known hotspots for ras activation in mouse liver tumors. These results, together with those from the National Toxicology Program study showing no evidence of cytotoxicity or genotoxicity by oxazepam, suggest that oxazepam preferentially promotes cells that have activating lesions other than ras.
Carcinogenesis 1994 May
PMID:Low frequency of H-ras mutations in hepatocellular adenomas and carcinomas and in hepatoblastomas from B6C3F1 mice exposed to oxazepam in the diet. 820 73

Clonal lines of transformed rat liver epithelial cells, derived from a single population of cloned diploid rat liver epithelial (stem-like) cell line (WB-F344) by exposure in vitro to N-methyl-N'-nitro-N- nitrosoguanidine (MNNG), produce hepatocellular carcinomas, hepatoblastomas and adenocarcinomas in syngeneic rats (Tsao and Grisham, Am. J. Pathol., 127, 168-181, 1987). In this study we show that these clonal lines demonstrate near-diploid (GN clones) or near-triploid (GP clones) aneuploidy and the universal occurrence of non-random chromosomal abnormalities. Marker chromosomes that involved four autosomes--a non-reciprocal translocation involving chromosomes 1 and 7 (t1q43;7q34), and addition of DNA of unknown origin to the pericentromeric regions of chromosomes 4 and 10--occurred in all of the cells of all transformed clones and in the cells of tumors that grew from them. New marker chromosomes involving the same regions of chromosomes 4 and 7 were found in several cell lines established from independent tumors. The preservation of marker chromosomes in tumor cells in the face of random loss and gain of other chromosomes suggests that these non-random aberrations were necessary for tumor formation. The presence of marker chromosomes was associated with increased expression of the c-myc gene (located at q34 on chromosome 7), the c-H-ras gene (located at q41-43 on chromosome 1) and the c-K-ras and TGF alpha genes (both located at unknown sites on chromosome 4), which we have previously shown to be highly correlated with tumorigenicity in these same transformed clonal lines (Lee et al., Cancer Res., 51, 5238-5244, 1992).
Carcinogenesis 1994 May
PMID:DNA contents and chromosomes of clonal lines of transformed rat liver epithelial cells and of cells from their derived tumors. 820 Jan 2

Chronic abuse of the analgesic drug phenacetin is associated with an increased risk of development of transitional cell carcinomas of the urinary tract. It is unclear whether phenacetin acts through chronic tissue damage (phenacetin nephropathy) or via a genotoxic metabolite causing promutagenic DNA lesions. In the present study, we investigated 15 urothelial carcinomas from 13 patients with evidence of phenacetin abuse. Tumors were screened for p53 mutations in exons 5-8 by single-strand conformation polymorphism (SSCP) analysis, followed by direct sequencing of PCR-amplified DNA. p53 Mutations were detected in 8/14 primary tumors (57%). All except one were missense mutations located in exon 5 (three mutations), exon 6 (one), exon 7 (two) and exon 8 (one). The type of mutation varied, with a preference for CpG sites. A frameshift mutation resulting from the insertion of a single cytosine at codons 151/152 was detected in a bladder tumor and its lung metastasis. Urothelial carcinomas located in the renal pelvis and in the ureter of the same patient exhibited two different mutations, strongly suggesting that they developed independently. Another patient had tumors in the renal pelvis and bladder, both of which contained the same p53 mutation, indicating intracavitary metastatic spread. This demonstrates that screening of p53 mutations allows the clonal origin of tumors in patients with multiple primary and metastatic lesions to be determined. None of the tumors investigated contained mutations in codons 12, 13 or 61 of H-ras or K-ras protooncogenes.
Carcinogenesis 1993 Oct
PMID:p53 mutations in phenacetin-associated human urothelial carcinomas. 822 64

LY171883, a peroxisome proliferator and leukotriene D4-antagonist, induced a statistically significant increase in the number of hepatic lesions in B6C3F1 female mice in a 2 year oncogenicity study at dietary doses of 0.0225% and 0.075%. The mutation frequency and spectrum of the 61st codon of H-ras was determined for 64 independent, archived lesions from the LY171883 2 year oncogenicity study using the polymerase chain reaction (PCR), allele specific oligo hybridization (ASO) and DNA sequencing. Results showed 41 (64%) of these lesions had mutations at the 61st codon (16/21 hepatocellular carcinomas, 4/10 hepatocellular adenomas, 19/26 focal hepatocellular hyperplasias and 2/7 focal hepatocellular atypia). These mutations consisted of 18 C-A transversions, 16 A-G transitions and seven A-T transversions. Compared to the mutation frequency for spontaneously occurring archival B6C3F1 hepatic lesions (41%), the frequency of LY171883 lesions (64%) was significantly higher (P < 0.01). The frequencies of H-ras 61st codon mutations among the LY171883 lesion types (hepatocellular carcinomas 76%, hepatocellular adenomas 40%, focal hepatocellular hyperplasias 73% and hepatocellular atypia 29%) were also significantly different (P = 0.035). In contrast, spontaneous lesions showed no statistical difference in the frequencies of mutation among lesion types (P > 0.5). The mutation spectrum of the LY171883 lesions was not significantly different from the spontaneous spectra. It may be concluded that based on the similarity in mutation spectrum and the increase in mutation frequency, LY171883 may selectively promote spontaneous hepatic lesions containing H-ras 61st codon mutations. In addition, the difference in mutation frequency among lesion types does not support a linear progression of all LY171883 lesions through focal atypia, focal hepatocellular hyperplasias, hepatocellular adenomas and hepatocellular carcinomas.
Carcinogenesis 1994 Feb
PMID:H-ras 61st codon activation in archival proliferative hepatic lesions isolated from female B6C3F1 mice exposed to the leukotriene D4-antagonist, LY171883. 831 27

In a previous study, the spectrum of H-ras mutations detected in B6C3F1 mouse liver tumors induced by 5, 50 or 150 mumol/kg body wt of N-nitrosodiethylamine (NDEA) was similar to that in spontaneous B6C3F1 mouse liver tumors, suggesting that activation of the H-ras gene in NDEA-induced mouse liver tumors may not be the direct result of the chemical interaction with the H-ras gene. In the present study, mutations in the H-ras oncogene from B6C3F1 mouse liver tumors induced by 5 or 50 mumol/kg body wt of NDEA were characterized by DNA amplification with polymerase chain reaction (PCR), single-strand conformation of polymorphism (SSCP) and direct sequence analysis. Twenty-one of 66 NDEA-induced B6C3F1 mouse liver tumors contained activated H-ras gene with 2 of 21 having a CG to AT transversion at the first base of codon 61, 17 of 21 having AT to GC transition and 2 of 21 having an AT to TA transversion at the second base of codon 61 in the H-ras gene. The predominant mutation, AT to GC transition (17/21, 81%) is consistent with the formation of O4-ethylthymine adduct, and is distinct from the predominant CG to AT transversion (50%) at the first base of codon 61 detected in H-ras gene from NDEA-induced B6C3F1 mouse liver tumors in a previous study by Stowers et al. Mutations in the K-ras oncogene from 59 A/J mouse lung tumors induced by 0.53 mmol/kg body wt of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were also characterized by using the above mentioned methods. Forty-six of 59 NNK-induced A/J mouse lung tumors contained activated K-ras genes. All 46 (100%) of the activated K-ras gene had GC to AT transitions at the second base of codon 12. The same mutation was observed in 70% (7/10) of the K-ras oncogene from A/J lung tumors induced by 4.8 mmol/kg body wt (given in 21 doses) of NNK. These data suggest that other factors in addition to genotoxic effect might be involved in the induction of rodent tumors by some carcinogens when given at higher doses. Therefore, further studies to compare the dose-dependent differences in the profile of ras mutations induced by chemical carcinogens may help to assess human cancer risk. Mutation(s) in exons 5-8 of the p53 gene was not found in these NDEA-induced mouse liver tumors and NNK-induced mouse lung tumors.
Carcinogenesis 1993 Aug
PMID:Dose-dependent ras mutation spectra in N-nitrosodiethylamine induced mouse liver tumors and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induced mouse lung tumors. 835 44

Using a combination of transplacental carcinogen exposure and retrovirus-mediated oncogene transfer into fetal brain transplants, we have studied complementary transformation by N-ethyl-N-nitrosourea (NEU) and the v-myc oncogene in the nervous system. Previous experiments had demonstrated that both agents will not induce tumors independently whereas simultaneous expression of v-H-ras and v-gag/myc exerted a powerful transforming potential in neural grafts. In order to identify other genetic alterations that co-operate with an activated myc gene, the neurotropic carcinogen NEU was used to generate mutations of cellular genes. On embryonic day 14 (ED14), pregnant donor animals (F344 rats) received a single i.v. dose of NEU (50 mg/kg). Twenty-four hours later (ED15), the fetal brains were removed, triturated and incubated with a retroviral vector carrying the v-gag/myc oncogene. Subsequently, these primary cell suspensions were transplanted stereotactically into the caudate-putamen of syngenic adult recipients. After latency periods of 3-6 months, 5 of 10 recipients harboring ED15 fetal brain transplants developed malignant, poorly differentiated neuroectodermal tumors in the grafts. No tumor development was observed in seven recipients harboring ED16 neural grafts. Cell lines were established from three tumors and the 110 kd gag/myc fusion protein encoded by the retroviral construct was identified in the tumors by Western blotting. Several candidate genes for mutational activation by NEU including the H-ras, K-ras and neu oncogenes were analyzed for specific point mutations by polymerase chain reaction (PCR) and direct DNA sequencing of the PCR products. However, no mutations were found in any of these genes. These findings lend further support to the multistep hypothesis of neoplastic transformation in the brain. The tumors induced in this model provide an interesting tool for the identification of genes that co-operate with an activated myc gene in neurocarcinogenesis.
Carcinogenesis 1993 Aug
PMID:Complementary tumor induction in neural grafts exposed to N-ethyl-N-nitrosourea and an activated myc gene. 835 58

Exposure of female inbred Sprague-Dawley Curl rats to intragastric 7,12-dimethylbenz(a)anthracene (DMBA) resulted in a variety of benign and malignant mammary tumors exhibiting a wide spectrum of proliferative activity as measured by [3H]-thymidine autoradiography. On the basis of earlier observations of 21% H-ras codon 61 mutations in DMBA-induced rat mammary tumors reported by Zarbl et al., the prevalence of this type of ras gene mutation was studied in relation to the rate of proliferation in individual benign and malignant tumors. In a series of 50 mammary tumors exhibiting highly different proliferation activities we did not detect any H-ras codon 61 mutations after allele-specific dot blot hybridization of PCR-amplified material obtained from paraffin sections. Neither mode of proliferation nor type of differentiation appears related to H-ras codon 61 mutations. The relevance of activated ras genes for rat mammary carcinogenesis appears restricted to model systems using N-methyl-N-nitro-sourea (MNU) as initiating carcinogen.
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PMID:Cell proliferation and prevalence of ras gene mutations in 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors. 835 38


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