Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of ras activation in the formation of spontaneous and chemically induced tumors was evaluated in the C3H mouse, a strain that has a low incidence of spontaneous lung tumors. Lung tumors were induced in C3H mice by treatment with 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 50 mg/kg, or nitrosodimethylamine (NDMA), 3 mg/kg for 7 weeks (3 times/week, i.p.). Eleven tumors from each treatment group were evaluated for activated ras genes by direct sequencing and oligonucleotide hybridization to slot blots of amplified DNA from these tumors. An activated K-ras gene was detected in 100% of NDMA- and NNK-induced lung tumors, and the activating mutation detected in all samples was a GC to AT transition (GGT to GAT) in codon 12. In contrast, only 40% of the seven spontaneous lung tumors analyzed contained an activated K-ras gene and the mutations identified were not localized to either a specific base or codon. Both NNK and NDMA can be activated via alpha-hydroxylation to methylating agents. The GC to AT mutation observed in codon 12 in the nitrosamine-induced tumors is consistent with the formation of an O6-methylguanine (O6MG) adduct. Similar concentrations (13-15 pmoles/mumol deoxyguanosine) of this promutagenic adduct were detected in lungs during treatment with either NNK or NDMA. Thus, both these nitrosamines appear to activate the K-ras gene in lung through a direct genotoxic mechanism involving the formation of the O6MG adduct. The frequency of K-ras activation was similar in chemically induced lung tumors from the sensitive A/J strain and the C3H mouse, indicating that susceptibility for neoplasia in these stains is not related to the ability to activate this gene. Although tumors were induced in lung from 100% of C3H mice following chronic carcinogen exposure, both the size and the multiplicity was significantly less, while latency was longer than that observed in the A/J mouse. These differences could not be attributed to an altered propensity for DNA damage, but rather suggest that genetic loci which regulate clonal expansion and growth of initiated cells play a major role in the susceptibility of pulmonary neoplasia.
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PMID:Role of ras protooncogene activation in the formation of spontaneous and nitrosamine-induced lung tumors in the resistant C3H mouse. 199 95

Malignant histiocytosis (MH) is a distinct disease entity defined clinically and morphologically. However, the neoplastic origin of MH is not well established. The authors report a 26-year-old woman who showed the typical clinicopathologic features of so-called MH. Cytogenetic and molecular genetic examinations were performed in addition to the morphologic and immunologic approach. The expression of CD2 and T-cell receptor gene rearrangements indicated the T-cell origin of this case. CD30, which is positive for anaplastic large cell lymphoma (Ki-1 lymphoma), was not expressed. The cytogenetic study revealed a clonal chromosome abnormality involving 3q25, 6p21, 11p15, and 11q21. An N-ras point mutation within codon 12 (GGT----GCT) was also detected. These finding indicate that MH defined clinically and morphologically is not a tumor of true histiocytic origin and that it should be reclassified on the basis of immunologic, cytogenetic, and molecular genetic data.
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PMID:A T-cell neoplasia showing clinicopathologic features of malignant histiocytosis with novel chromosomal abnormalities and N-ras mutation. 200 29

In conclusion, we report the cases of two patients with large hemangiomas of the liver, abdominal pain, increased ESR and fibrinogen, increased serum alkaline phosphatase and gamma-glutamyltransferase activity, and normal white blood cell counts. Clinical and biochemical abnormalities disappeared after surgical resection. Increased ESR and fibrinogen are probably related to thrombosis within the tumor. This mode of presentation may suggest a diagnosis of hepatocellular carcinoma.
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PMID:Giant hemangioma of the liver with pain, fever, and abnormal liver tests. Report of two cases. 200 71

Point mutation in codons 12, 13 and 61 of the K-ras oncogene in gastric epithelial tumors were investigated by polymerase chain reaction from sections of formalin-fixed, paraffin-embedded tissue followed by dot-blot hybridization with mutation-specific oligonucleotide probes. Point mutations were found specifically in four of 20 tumors of intestinal histological subtype; GGT to GAT in three cases and to GTT in one case, all in codon 12 of K-ras. These mutations were also confirmed by direct sequencing. In contrast, none of 11 diffuse-type tumors showed K-ras point mutations. While K-ras point mutations may not be frequent events in gastric tumorigenesis, the similarity of the intestinal-type gastric tumors and colorectal tumors for K-ras point mutations as well as the association of mutations in K-ras with a particular gastric tumor histology implicates K-ras activation in the development of these tumors.
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PMID:K-ras activation in gastric epithelial tumors in Japanese. 204 76

The role of the Clara and type II cell in the development of pulmonary tumors in the A/J mouse and Fischer rat was investigated by determining the relationship of DNA methylation and repair in pulmonary cells to oncogene activation and by characterizing the morphology of pulmonary tumors induced by treatment with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Marked differences in the formation of the promutagenic adduct O6-methylguanine (O6MG) were observed in pulmonary cells following treatment of rats with NNK. Concentrations of this adduct in Clara cells greatly exceeded (3- to 30-fold) those detected in type II cells and whole lung with doses of NNK ranging from 0.1 to 50 mg/kg. In addition, very low rates of repair of this adduct were detected in Clara cells, whereas efficient adduct removal occurred in type II cells. The importance of this adduct and the role of cell specificity was suggested by the fact that a strong correlation was observed between the concentration of O6MG in Clara cells and tumor incidence in the Fischer rat with doses of NNK ranging from 0.03-50 mg/kg. In contrast, no differences in adduct concentration between type II and Clara cells from A/J mice were observed under conditions resulting in pulmonary tumor formation. Activation of the K-ras gene was detected in lung tumors from A/J mice. This gene was activated by a mutation in codon 12 involving a GC to AT transition (GGT to GAT) and is consistent with base mispairing produced by the formation of O6MG. Activation of this gene was not associated with lung tumor formation in the Fischer rat. DNA from rat lung tumors did induce tumors in the nude mouse carcinogenicity assay. In addition, rat repetitive sequences were detected in DNA isolated from these nude mouse tumors. In spite of the cell selectivity for DNA methylation in Clara cells from rat and the relationship between O6MG formation and tumorigenicity, early proliferative lesions observed in both mice and rats involved the alveolar areas. Ultrastructural examination of these lesions and adenomas revealed morphologic features characteristic of the type II cell. Thus the lack of agreement between biochemical and morphological findings makes it difficult to hypothesize a cell of origin for the pulmonary neoplasms induced by NNK. However, these studies indicate that the concentration of O6MG in Clara cells is an excellent indicator of the carcinogenic potency of NNK in the rat.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of Clara cells and type II cells in the development of pulmonary tumors in rats and mice following exposure to a tobacco-specific nitrosamine. 205 30

This study was undertaken to investigate the influence of dietary vitamin A deficiency and type of diet on tetrachlorodibenzo-p-dioxin (TCDD)- and phenobarbital-induced liver tumor promotion in rats. Female Sprague-Dawley rats were partially hepatectomized and subsequently initiated with nitrosodiethylamine. One week later the rats were allocated to five different dietary regimens for the duration of the study: three purified (casein-based) diets containing 200, 1200, and 10000 IU vitamin A per kilogram, respectively, and two conventional (cereal-based) rat diets containing 2000 and 14000 IU vitamin A per kilogram, respectively. After an additional 4 weeks, groups of rats on each dietary regimen were started on one of four different promoter treatments: 0.07 micrograms TCDD/kg/week (sc); 0.7 micrograms TCDD/kg/week (sc); 500 ppm phenobarbital in the drinking water or vehicle only (arachis oil, sc). The study was terminated after 16 weeks of promoter treatment. Sections of liver were stained for gamma-glutamyltranspeptidase (GGT) activity and GGT-positive altered hepatic foci (AHF) were evaluated by stereological methods. All factors studied (TCDD, phenobarbital, dietary vitamin A content, and the type of diet) were shown to influence AHF development significantly. As expected, TCDD and phenobarbital enhanced foci development. Vitamin A deficiency enhanced foci development in its own right and increased the TCDD-induced response markedly. Dietary vitamin A content did not modulate phenobarbital promotion of AHF in the same manner. The enhancement of TCDD-induced effects on foci development by vitamin A deprivation was accompanied by an increased incidence of histological changes marking degeneration in the liver (e.g., oval cell hyperplasia) and accentuation of other TCDD-related toxic responses. In addition, the groups of rats maintained on the cereal-based diets and subjected to the various promoter/vitamin A regimens exhibited significantly higher AHF incidence as compared to correspondingly treated rats fed the purified, casein-based diets. In conclusion, vitamin A deficiency alone may promote hepatocarcinogenesis and enhance the promoting effect of TCDD treatment. However, TCDD-induced depletion of hepatic vitamin A stores was not implicated as a major cause of promotion by TCDD. Nevertheless, vitamin A deficiency brought about by TCDD alone may well act as a promotive stimulus concertedly with an as yet unidentified cellular mechanism in TCDD-induced liver tumor promotion. The differential effects of the two types of diets recorded in the study remain undocumented.
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PMID:Modulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin and phenobarbital-induced promotion of hepatocarcinogenesis in rats by the type of diet and vitamin A deficiency. 205 68

The molecular genetics of human endometrial carcinoma have yet to be defined to any significant extent. Cell lines from 11 endometrial carcinomas were examined for alterations in proto-oncogenes that might predictably be present, based on existing data from the better-characterized human carcinomas of the uterine cervix, ovary, and breast. Codons 12, 13, and 61 of the Ha-ras, Ki-ras, and N-ras genes were examined for possible point mutations, and the c-erbB2/neu, c-myc, and epidermal growth factor receptor (EGFR) genes were examined for amplification or overexpression. Ras mutations were found in seven of 11 (64%) tumors, including three in codon 61 of Ha-ras (CAG----CAT) and four in codon 12 of Ki-ras (GGT----GAT in two and GGT----GTT in two). No evidence was found for amplification or overexpression of the c-erbB2 or EGFR genes in any tumor. One tumor contained amplified c-myc sequences and exhibited relative overexpression of c-myc. These data suggest that the amplification or overexpression of several proto-oncogenes frequently observed in other human gynecologic and breast tumors are not prevalent in endometrial carcinoma and that ras gene mutations are relatively common in this tumor type.
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PMID:Analysis of oncogene alterations in human endometrial carcinoma: prevalence of ras mutations. 206 24

Our previous studies have shown that human skin cancers occurring on sun-exposed body sites frequently contain activated Ha-ras oncogenes capable of inducing morphologic and tumorigenic transformation of NIH 3T3 cells. In this study, we analyzed human primary squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) occurring on sun-exposed body sites for mutations in codons 12, 13, and 61 of Ha-ras, Ki-ras, and N-ras oncogenes by amplification of genomic tumor DNAs by the polymerase chain reaction, followed by dot-blot hybridization to synthetic oligonucleotide probes designed to detect single base-pair mutations. In addition to the primary human skin cancers, we also analyzed Ha-ras-positive NIH 3T3 transformants for mutations in the Ha-ras oncogene. The results indicated that all three NIH 3T3 transformants, 11 of 24 (46%) SCCs, and 5 of 16 (31%) BCCs contained mutations at the second position of Ha-ras codon 12 (GGC----GTC), predicting a glycine-to-valine amino acid substitution, whereas only 1 of 40 skin cancers (an SCC) displayed a mutation in the first position of Ki-ras codon 12 (GGT----AGT), predicting a glycine-to-serine amino acid change. In addition, three of the SCCs contained highly amplified copies of the N-ras oncogene in their genomic DNA. Interestingly, two of the SCCs containing amplified N-ras sequences also had G----T mutations in codon 12 of the Ha-ras oncogene. These studies demonstrate that mutations in codon 12 of the Ha-ras oncogene occurred at a high frequency in human skin cancers originating on sun-exposed body sites, whereas mutation in codon 12 of Ki-ras or amplification of N-ras occurred at a low frequency. Since the mutations in the Ha-ras and Ki-ras oncogenes were located opposite potential pyrimidine dimer sites (C-C), it is likely that these mutations were induced by ultraviolet radiation present in sunlight.
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PMID:Ras gene mutation and amplification in human nonmelanoma skin cancers. 206 25

Two hepatoma cell lines designated Kagura-1 and Kagura-2 were established from rat hepatocellular carcinomas induced by aflatoxin B1, and have been propagated for over two years. Both cell lines grew as monolayered sheets with a population doubling time of about 20 h. Chromosome counts of Kagura-1 cells ranged from 34 to 45 with a modal number of 40, while that of Kagura-2 cells ranged widely from 40 to 130 with a modal number of 65. Subcutaneous inoculation of cultured cells of both these lines into nude mice resulted in tumor formation. The histopathological appearances of the induced tumors were similar to those of the original tumors. Kagura-1 and Kagura-2 cell lines express at least two tumor markers, glutathione-S-transferase P and gamma-glutamyl transpeptidase; the level of c-myc messenger ribonucleic acid was also highly elevated.
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PMID:Establishment and characterization of cell lines (Kagura-1 and Kagura-2) from aflatoxin B1-induced rat hepatoma. 211 Aug 69

Resident peritoneal macrophages incubated with 3.5 x 10(-7) M Calcium ionophore A23187 in tumor cell growth medium (TGM) release large amounts of leukotriene (LT)E4 and an unidentified 5-lipoxygenase product, whereas A23187-stimulated macrophages produce in serum free medium LTD4, predominately. LTC4 and 3H-LTC4 incubated for 20 min at 37 degree C in serum containing TGM, convert into LTE4 and 3H-LTE4, respectively. Thus, LTC4 released from A23187-stimulated macrophages is an intermediate in TGM which rapidly converts into LTE4, probably because of the presence of gamma-glutamyl transpeptidase and cystenylglycinase in TGM. Macrophages express antitumor cytostatic activity towards P815 cells (49-53%) in a cocultured ratio (macrophage: tumor cell) 2:1 when stimulated with 3.5 x 10(-7) M A23187 in TGM. The 5-lipoxygenase inhibitor AA861 reverses the cytostatic activity by 42-58% and it inhibits also the formation of A23187-induced 5-lipoxygenase products from macrophages. Restoration of 38% macrophage- antitumor cytostatic activity by exogenous LTC4 (10(-8) M) indicates that LTC4 is an essential 5-lipoxygenase intermediate in the pathway of required signals underlying A23187-induced macrophage antitumor cytostatic activity. Macrophages not stimulated by A23187 do not express cytostatic activity in the presence of LTC4. This implies that besides LTC4, increased cytosolic [Ca2+] is required for A23187 induction of macrophage cytostatic activity.
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PMID:Leukotriene C4 is an essential 5-lipoxygenase intermediate in A23187-induced macrophage cytostatic activity against P815 tumor cells. 211 58


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