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

Neonatal treatment with estrogens is associated with development of uterine adenocarcinomas in CD-1 mice. Treatment with the synthetic estrogen diethylstilbestrol (DES) on Days 1 to 5 after birth results in 90% incidence of these hormone-dependent lesions in 18-mo.-old mice. Three cell lines were established from these DES-associated tumors. Each of these cell lines exhibited morphologic and ultrastructural characteristics of transformed epithelial cells, including an increased nuclear:cytoplasmic ratio, enlarged and irregular nuclei with multiple nucleoli and areas of chromatin condensation, positive staining for cytokeratin, desmosomes, and microvilli. After subcutaneous injection into nude mice, all three cell lines formed solid tumors within 4 wk. Although the primary uterine tumors and tumor transplants in nude mice had been shown to be estrogen-dependent and estrogen-receptor positive, neither the monolayer growth nor the tumorigenicity of any of the three cell lines in this study was enhanced by or dependent on estrogen. Estrogen receptor levels were low in early and intermediate passage cells. Allele-specific oligonucleotide hybridization analysis of PCR-amplified cell line DNA revealed no point mutations in the 12th, 13th, or 61st codons of the K-ras or H-ras protooncogenes. Southern analysis revealed no changes in genomic organization of the putative tumor suppressor gene DCC, but demonstrated a three- to four-fold amplification of the c-myc gene in one cell line. Expression of c-myc RNA was concomitantly increased in the same cell line. These three transformed cell lines represent the end point in the process of hormone-associated tumorigenesis and as such should prove useful in investigating the molecular changes and the mechanisms involved in hormonal carcinogenesis.
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PMID:Characterization of murine cell lines from diethylstilbestrol-induced uterine endometrial adenocarcinomas. 159 5

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

The multistep aspects of carcinogenesis including initiation and promotion problems in both human and experimental hepatocarcinogenesis are discussed, especially in terms of oncogene and antioncogene changes. It is shown that the H-ras activation may be an event occurring in relatively late phase of carcinogenesis in the mouse systems, and that hepatitis B integration frequently causes host chromosomal rearrangement possibly leading to inactivation of cancer suppressor genes. In addition, significance of endogenously-produced nitrosamines in hepatocarcinogenesis is pointed out.
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PMID:[Pathogenesis of human cancer]. 165 95

RNA expressions of common integration site (int) genes and several oncogenes were investigated in mammary carcinomas spontaneously developed in different three strains of mice; DD/Tbr, NIH Swiss and BALB/c which harbor DD-MMTV derived from DD/Tbr mouse. Latter two strains of mice were designated NIH/Mtv+ and BALB/Mtv+, respectively. An increased expression of int-1 (wnt-1) and int-2 genes was observed in 56% (9/16) and 50% (8/16) of mammary carcinomas of DD/Tbr mice, respectively. Either int-1 or int-2 RNAs were expressed in 81% (13/16) of the carcinomas of DD/Tbr mice. IN NIH/Mtv+ mice, activation of int-1 and int-2 was observed in 41% (7/17) and 24% (4/17) of mammary carcinomas, respectively. Either int-1 or int-2 RNAs were expressed in 47% (8/17) of the carcinomas examined in this strain. In BALB/Mtv+ mice, on the other hand, either int-1 or int-2 gene were transcribed into RNAs at low frequency (33%: 3/9). These results suggest that the frequency of activation of int genes in mammary carcinomas induced by the same DD-MMTV in three strains of mice is genetically defined characteristics of these strains, and that the involvement of int-1 and int-2 genes in virus-induced mammary carcinogenesis may be influenced by genetic properties of animals. The activation of int-1 and int-2 genes did not clearly correlate with an increase in the expression of oncogenes examined; H-ras, K-ras, N-ras, myc, raf, fgr, fms, erB, mos, and src genes.
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PMID:The different activation of int genes in mammary carcinomas developed in three mouse strains harboring mouse mammary tumor viruses derived from DD/Tbr. 166 Aug 18

We have developed transgenic mice that inherit albumin promoter-regulated simian virus 40 (SV40) large T-antigen gene, expressed specifically in hepatocytes. These mice all develop multifocal hepatocellular carcinomas (HCCs) at around 5 months and die of liver insufficiency by 7 months in remarkable synchrony. The liver tissue appears normal in the initial 3 weeks, and thereafter rapid cytomegalic degeneration of original hepatocytes, proliferation of quasi-regenerative hepatocytes, neoplastic cell foci, nodules and finally HCCs develop in sequence. Considerable variation existed both in morphological and enzymatic features and in T-antigen expression among neoplastic lesions, including carcinomas. Oligonucleotide hybridization studies revealed activating point mutations of the c-H-ras oncogene in 40% (10/25) of tumors obtained at around 6 months. The positive signals were, however, considerably weaker in half of them suggesting that such tumors comprised cells both with and without ras mutation. Sequential observation of culture cell lines established from tumors also revealed the appearance of activated c-H-ras with time, which was associated with biological progression. Thus, in this model system, ras activation may be an event occurring in a relatively late phase of carcinogenesis associated with progression of tumors. Karyotype analysis of cell lines revealed remarkable chromosomal instability. In studies of sister chromatid exchange in hepatocytes, twice as frequent occurrence was demonstrated in transgenic mice as in their counterpart hepatocytes. Thus T-antigen may be contributing as a mutagen to the hepatocarcinogenesis, in addition to its cytotoxic and growth modifying activities.
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PMID:Multistep hepatocarcinogenesis in transgenic mice harboring SV40 T-antigen gene. 166 91

The Harvey ras locus was examined for restriction fragment polymorphism and loss of allelic heterozygosity in 62 oral cancer patients. Southern blot analysis on BamHI digests of the tumour tissue DNA, revealed 23 patients with H-ras-1 heterozygosity. The probes used to study the polymorphism were the BamHI 6.6-kb fragment encoding the complete H-ras-1 sequence plus the variable tandem repeat (VTR) region, and the 1-kb MspI fragment encoding the VTR region. The allelic heterozygosity was better resolved by PvuII and further confirmed by TaqI. In addition, TaqI digestion demonstrated a unique VTR rearrangement indicated by 2.1-kb, 0.9-kb and 0.6-kb fragments, implying additional TaqI sites, in three of the patients. Further analysis of matched tumor tissue and peripheral blood cell DNA from the same patient demonstrated tumor-associated loss of one of the allelic fragments in 7/23 (30%) of the patients with H-ras-1 heterozygosity. However, the loss was not significantly correlated to clinicopathological parameters staging the disease. Thus, our data showing loss of H-ras-1 alleles and VTR rearrangement, with relatively high incidence (9/23; 39%) in the oral cancer patients at various stages of the disease, implies H-ras-1 involvement as an early event in the process of oral carcinogenesis.
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PMID:Loss of allelic heterozygosity at the harvey ras locus in human oral carcinomas. 167 60

Malignant melanoma tumors are inherently resistant to anticancer drugs, yet the mechanism of this resistance is not understood. B16 melanoma, a spontaneous tumor which arose in the C57BL/6 mouse; BL6 melanoma, a highly invasive variant; and Mel-ab melanocytes, isolated from C57BL/6 mouse skin, were examined for intracellular glutathione (GSH) content. GSH was higher in BL6 and B16 cells than in Mel-ab cells, with the highest concentration in BL6 cells. Since GSH is thought to be involved in the resistance of many cells, including melanoma, to cytotoxic drugs, we determined whether intracellular GSH content was altered during transformation of Mel-ab cells. After transfection with pHO6T1 plasmid DNA, containing an activated c-H-ras oncogene flanked by transcriptional enhancers, 1.3% of successfully transfected Mel-ab melanocytes formed distinct colonies in soft agar, compared to 0.2% of cells transfected with control pHO6 plasmid without H-ras. Approximately 53% of the pHO6T1-transfected colonies isolated from soft agar grew in 5% CO2 in the absence of phorbol-12-myristate-13-acetate, a requirement for the extended growth of Mel-ab cells. Cells transfected with control pHO6 plasmid and non-transfected Mel-ab cells did not survive under these conditions. All of the isolated pHO6T1 transfected cells formed tumors when inoculated into C57BL/6 mice. Transformed cells had higher GSH content than non-transfected Mel-ab cells, whether expressed on a cellular or cell volume basis. Although the amount of oxidized glutathione was greater in the tumorigenic cells, this could not account for the overall increase in GSH. Neither glutathione S-transferase nor gamma-glutamyl transpeptidase activities were increased in the H-ras-transfected cells. Northern blot analysis confirmed H-ras-specific RNA in pHO6T1-transformed cells.
Carcinogenesis 1991 Jul
PMID:Induction of glutathione content in murine melanocytes after transformation with c-H-ras oncogene. 171 78

We have been studying a rat model of colon cancer in which tumors are induced by direct application of N-methyl-N-nitrosourea (MNU) to discrete areas of the colonic mucosa for a limited period of time. Activation of the ras genes by point mutation has been observed in many experimental tumors, including tumors induced by MNU. To detect potential activating point mutations in the H-ras and K-ras oncogenes in MNU-induced rat colon tumors, DNA samples from 40 adenomas, nine carcinomas, and 14 histologically normal tissue samples from 14 rats--as well as from 16 foci induced on NIH3T3 cells by tumor DNAs--were amplified by the polymerase chain reaction and hybridized with allele-specific oligonucleotide probes. No H-ras point mutations were observed in any of these samples. We did detect K-ras point mutations, however, in four primary tumours--one adenoma (2.5%) and three carcinomas (33%); these mutations were all G----A transitions at the second nucleotide of codons 12 and 13. The absence of detectable ras mutations from the majority of tumors suggests that, in contrast to other animal models utilizing MNU, tumorigenesis in MNU-induced rat colon tumors may predominantly involve activation of genes other than ras.
Carcinogenesis 1992 Jan
PMID:K-ras oncogene mutations in rat colon tumors induced by N-methyl-N-nitrosourea. 173 72

In a study of the mechanisms involved in the induction of tumours by chemicals, the Ha-ras oncogene was analysed in liver tumours induced by the genotoxic carcinogen diethylnitrosamine (DEN), or the non-genotoxic agent phenobarbitone (PB) in C3H/He mice. Mutations were detected using the polymerase chain reaction and oligonucleotide hybridization. Codon 61 mutations were detected in 41% of DEN-induced tumours (19/46), either in the first base (CG----AT, 12/19), a transversion, or the second base (AT----GC, 7/19), a transition. Codon 61 mutations were also found in 29% of spontaneous tumours (all CG----AT, 6/21) but none were detected in PB-induced tumours (0/15) or in normal liver tissue of untreated mice (0/30). No mutations were detected at codon 12. Low and variable expression of the Ha-ras gene was detected in all liver tissues with moderately raised levels (175-200%) in spontaneous, DEN and PB-induced tumours as compared to normal liver tissue. The H-ras gene was methylated to some extent in all liver tissues, with no discernible difference between the treatments. The frequency of the Ha-ras mutation at codon 61 in DEN-induced tumours is greater than in spontaneously arising tumours. This increase is not accompanied by any specific alteration in the expression or methylation of the gene. Since PB-induced tumours do not possess mutations in the Ha-ras gene at codons 12 or 61, the data suggest that the non-genotoxic agent PB induces tumours in the C3H/He mouse liver with a mechanism distinct from that of spontaneous tumours or those that result from treatment with a potent genotoxic carcinogen such as DEN.
Carcinogenesis 1991 Dec
PMID:Analysis of the Ha-ras oncogene in C3H/He mouse liver tumours derived spontaneously or induced with diethylnitrosamine or phenobarbitone. 174 36

Activation of the ras oncogene was investigated in esophageal tumors induced by methylbenzylnitrosamine (MBN) in the Sprague-Dawley rat. DNA was extracted from grossly visible carcinogen-induced tumors. H-ras and K-ras gene sequences were then amplified by the polymerase chain reaction. Point mutations in the ras genes were then identified by selective hybridization to allele-specific oligonucleotide probes. A guanine to adenine transition at the 35th nucleotide in the H-ras coding sequence (GGA to GAA in the 12 codon) was observed in 67% (10 of 15) of the papillomas examined. This mutation codes for glutamate instead of glycine as the 12th amino acid of the ras p21 protein. No other H-ras or K-ras mutations were observed. To determine the distribution of this H-ras mutation in esophageal tissues, histological sections of MBN-treated esophagi were stained with a monoclonal antibody (E184) which selectively recognizes the mutated ras p-21 with glutamate substituted for glycine as the 12th amino acid. Expression of the mutant ras p21 protein was observed in 20% of the squamous papillomas, 13.6% of hyperplastic lesions and 10% of dysplastic lesions. Thus, activation of the H-ras oncogene as a result of guanine to adenine point mutation is a frequent event in esophageal tumors induced by MBN, occurring in 67% of squamous papillomas, but expression of the corresponding mutant ras p21 protein is observed in a much smaller proportion of the tumors in this animal model.
Carcinogenesis 1991 Dec
PMID:Incidence of Harvey ras oncogene point mutations and their expression in methylbenzylnitrosamine-induced esophageal tumorigenesis. 174 41


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