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)

A single local injection of 2.5 mumol of N-hydroxy-N-formyl-2-aminofluorene (N-hydroxy-FAF), N-hydroxy-N-acetyl-2-aminofluorene (N-hydroxy-AAF), or N-hydroxy-N-pro-pionyl-2-aminofluorene )N-hydroxy-PAF) to each of the six left mammary glands of female Sprague-Dawley derived CD rats gave a mammary tumor incidence, after 12 months, of 53% for the N-acetyl (42% adenocarcinoma, 11% fibroadenoma), 41% for the N-formyl (8% adenocarcinoma, 11% sarcoma, 22% fibroadenoma), and 33% for the N-propionyl (11% adenocarcinoma, 22% fibroadenoma) derivatives of N-hydroxy-N-2-aminofluorene, Latent periods for malignant tumor appearance (adenocarcinoma or sarcoma) was 210 days, 148 days, and 177 days, respectively, with no malignant tumors occurring in the vehicle-treated animals. In contrast, latent periods for benign tumor appearance (fibroadenoma) was 263 days for control animals, 289 days for the N-hydroxy-AAF, 324 days for the N-hydroxy-FAF, and 317 days for the N-hydroxy-PAF animals. When N-acetyl-2-aminofluorene (AAF) was applied as above there was only an 8% mammary tumor incidence (4% adenocarcinoma, 4% fibroadenoma) with a latent period of 207 days for malignant tumor (adenocarcinoma) and 221 days for benign tumor (fibroadenoma) appearance. Arylhydroxamic acid N, O-acyltransferase activity has been demonstrated in the mammary glands of male, and lactating and non-lactating female Sprague-Dawley derived CD rats by means of nucleic acid binding assay. Mammary gland cytosol catalyzed tRNA adduct formation to a greater extent with N-hydroxy-FAF. AAF was not activated by this enzyme. Ammonium sulfate fractionation demonstrated the presence of two enzymes, one specific for N-hydroxy-FAF (70-80% fraction), the other specific for N-hydroxy-AAF and N-hydroxy-PAF (40-70% fraction). Moreover, gel filtration chromatography of mammary gland cytosol demonstrated the presence of two enzymes of differing acyl specificity. Mammary gland microsomes catalyzed the formation of tRNA adducts, but only with the N-hydroxy-FAF derivative. Assays that tested the mutagenic potential of the arylhydroxamic acids in Salmonella typhimurium TA-1538 with either mammary gland cytosol or microsomes demonstrated the order of mutagenicity to be N-hydroxy-FAF greater than N-hydroxy-AAF greater than N-hydroxy-PAF. A similar order of mutagenicity was demonstrated without an external metabolic activation system. These data demonstrate that the presence of two distinct enzymes in the rat mammary gland that activate arylhydroxamic acids.
Carcinogenesis 1982
PMID:Rat mammary gland carcinogenesis after local injection of N-hydroxy-N-acyl-2-aminofluorenes: relationship to metabolic activation. 708 66

Phagocytic indices of 17 nickel compounds were measured in vitro in monolayer cultures of rat peritoneal macrophages. The macrophages were exposed for 1 h at 37 degrees C to particles (1.5 micrometer median diameter) of the nickel compounds, at concentrations of 10 microgram/ml of medium (2 microgram/cm2 of monolayer). Phagocytic induces (i.e., the percentages of macrophages with one or more engulfed particles) ranged from 69% (NiO) to 3% (amorphous NiS). In order to decreasing phagocytic indices, the 17 nickel compounds were ranked as follows: NiO greater than Ni4FeS4 greater than NiTiO3 greater than NiSe greater than alpha Ni3S2 greater than Ni greater than Ni5As2 greater than NiS2 greater than NiFe alloy greater than NiSb greater than Ni11As8 greater Ni3-Se2 greater than beta NiS greater than NiTe greater than NiAs greater than NiAsS greater than amorphous NiS. Rank-correlation (P less than 0.03) was observed between the phagocytic indices of the nickel compounds and their dissolution half-times in rat serum. Nickel subsulfide, alpha Ni3S2, was a notable exception to the general concordance between phagocytic indices and dissolution half-times: alpha Ni3S2 was avidly phagocytized by macrophages, yet it had one or the shortest dissolution half-times. Preliminary results of carcinogenesis tests of 14 of the nickel compounds do not indicate significant rank-correlation between the phagocytic indices of the nickel compounds and the sarcoma incidences at 1 yr after i.m. administration of the compounds to rats.
Carcinogenesis 1982
PMID:Phagocytosis of particulate nickel compounds by rat peritoneal macrophages in vitro. 708 73

Asbestos samples were injected into the right pleural cavity of random-bred rats (20 mg thrice monthly). Milled commercial chrysotile induced pleural mesotheliomas in 65.5%, its dust in 46.3%, milled synthetic chrysotile in 2.4%, milled commercial magnesia-arphvedsonite in 77.1%, milled commercial anthophyllite in 41.4%, its dust in 64.9% and milled synthetic hydroxyamphibole in 54.5%. Intratracheal injections (10 mg twice monthly) of milled commercial chrysotile into Syrian golden hamsters induced lung tumours in 63% (malignant in 44.4%, benign in 18.5%), synthetic chrysotile in 23% (malignant in 7.7%, benign in 15.3%), commercial magnesia-arphvedsonite (5 mg twice monthly) in 80.8% (malignant in 46.2%, benign in 34.6%) and synthetic hydroxyamphibole (5 mg twice monthly) in 63.4% (malignant in 19.2%, benign in 44.2%). Benzo[a]pyrene adsorbed or added to asbestos dust stimulated asbestos-induced lung carcinogenesis in rats but had no influence on pleural carcinogenesis. Pretumorous lesions were found in lung tissue and in pleural mesothelium in all experiments in rats, hamsters and monkeys after instillations of asbestos into the lungs and pleural cavity. The morphological picture of the pretumorous lesions and tumours was similar in all experiments. Diffuse and focal hyperplasia and proliferation of epithelium-like and fibroblast-like mesothelial cells were observed. Benign (adenoma-like, fibrous) and malignant (carcinoma-like, sarcoma-like, mixed) mesotheliomas were also found.
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PMID:Pretumorous lesions and lung and pleural tumours induced by asbestos in rats, Syrian golden hamsters and Macaca mulatta (rhesus) monkeys. 723 54

Cells from a C57BL/cbi chemically induced fibrosarcoma (FS6) require exogenous platelet-derived growth factor (PDGF) for in vitro proliferation (as do normal "untransformed" fibroblasts) whereas cells obtained from the FS6M1 tumour, a spontaneous metastasizing subline, show autonomy from PDGF in vitro. Furthermore, the FS6 cells exhibit very low colony formation in an anchorage-independent growth assay. In vivo, this tumour is immunogenic, rarely metastasizes and is heavily infiltrated by host macrophages. Studies of in vitro cell proliferation and anchorage-independent growth show that syngeneic host macrophages from the peritoneal cavity or from the growing tumour release a diffusible factor(s) which has (1) growth-stimulating activity on FS6 cells in monolayer cultures in PDGF-poor medium and (2) potent colony-stimulating activity on FS6 cell cultured in methyl-cellulose-containing medium. These macrophage supernatants stimulate proliferation of quiescent normal fibroblasts in monolayer culture as well as FS6 sarcoma cells, but do not stimulate anchorage-independent growth of normal cells. Supernatants from BCG-elicited macrophages were shown to contain abundant arginase, and were cytolytic to FS6 cells but not to normal cells. Heat inactivation abrogated the arginase and cytotoxicity, revealing heat-stable mitogenicity for FS6 cells and normal fibroblasts. The stimulatory effect of macrophages on FS6 sarcoma cells can be mimicked by the addition of the tumour promoter 12-tetradecanoyl-phorbol-13-acetate (TPA) and supports the hypothesis that macrophages could play a significant role in multistage carcinogenesis by providing a source of endogenous promoter.
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PMID:Promotion of fibrosarcoma cell growth by products of syngeneic host macrophages. 729 7

The glucuronic acid conjugate of N-hydroxy-4-aminobiphenyl was tested for carcinogenicity using a heterotopically transplanted rat urinary bladder (HTB) diverted from urine flow. A low-grade transitional cell carcinoma developed in 1 of 16 HTB and sarcoma surrounding the Ommaya reservoir connected to HTB in 8 of 16 rats. This unexpected high incidence of sarcomas, not previously observed in HTB-carcinogenesis model, suggested that the glucuronide conjugate of N-hydroxy-4-aminobiphenyl is a locally active carcinogen to mesenchymal cells.
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PMID:Development of sarcomas in heterotopically transplanted rat urinary bladder unit exposed to glucuronic acid conjugate of N-hydroxy-4-aminobiphenyl. 729 24

The s.c. infection of 10 mg benzo(a)pyrene dissolved in 1 ml tricaprylin induced in Wistar rats local malignant tumors, such as fibrosarcoma, rhabdomyosarcoma, and polymorph cell sarcoma. The growth of the tumors was relatively rapid, reaching weights of 140-155 g before rats died 142-168 days after the administration of the carcinogen. On the contrary, under the same experimental conditions, high doses of Vitamin C about 525 mg/day/rat administered orally in drinking water (total amount of Vitamin C 55 g/rat corresponding to 40% of their body weight ) inhibited to a great extent the benzo(a)pyrene carcinogenesis. Only one slowly growing rhabdomyosarcoma (13 g of weight) was developed showing characteristic damage of malignant cells and partial replacement of the neoplastic area with granuloma tissue. The significance ov Vitamin C for cancer prevention and treatment is discussed.
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PMID:Inhibition of benzo(a)pyrene carcinogenesis in rats with vitamin C. 740 Feb 11

Tenascin, a novel six-armed extracellular-matrix glycoprotein, is expressed in a temporally and spatially restricted pattern during carcinogenesis in association with stromal-epithelial interactions. In this study, we have tested the hypothesis that tenascin expression depends upon the change of the cellular environment from in vitro to in vivo. The distribution and alterations in the expression of tenascin were compared between in vitro and in vivo studies in a variety of human epithelial- and nonepithelial-derived cell lines. When cell lines were transplanted into nude mice, all xenografts induced host-mouse-stroma-derived tenascin. Four carcinoma-derived cell lines and all sarcoma-derived lines, which secreted tenascin in vitro, were found to produce human tenascin after transplantation. Furthermore, three carcinoma-derived cell lines, A431, HEp-2, and MCF7, which did not synthesize tenascin in vitro, did synthesize human tenascin after transplantation. These tenascin nonproducing carcinoma cell lines did not express tenascin mRNA in vitro. The addition of TGF-beta 1 to the culture medium induced the synthesis and secretion of tenascin, but TGF-beta 2 and bFGF were less effective. TGF-beta 1 also induced other extracellular-matrix components, fibronectin and laminin. TGF-beta 1 did not induce tenascin in tenascin nonproducing carcinoma cell lines, such as WiDr and A549, in which human tenascin was not induced after transplantation. We have established an in vitro system in which tenascin is induced by the diffusible factor TGF-beta 1. This system could shed light on the mechanism of induction of human tenascin observed in vivo in tenascin nonproducing carcinoma cell lines.
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PMID:Tenascin induction in tenascin nonproducing carcinoma cell lines in vivo and by TGF-beta 1 in vitro. 751 13

Macroscopic stomach tumors induced in Sprague-Dawley rats during two chronic bioassays with the acetanilide herbicide butachlor at a dietary concentration of 3000 ppm, were evaluated histologically and immunohistochemically in order to determine their identity and pathogenesis. The tumors, which occurred primarily in female rats, were a heterogeneous series, including a few consisting wholly or partly of classic solid or anaplastic epithelium, but with the majority containing diffusely distributed primitive neoplastic cells. The latter had either the general appearance of undifferentiated epithelium or presented a more "mesenchyme-like" pattern where the cells were epithelioid, blastema-like, neuroendocrine-like or sarcoma-like with fascicular disposition. Gastric glandular profiles were also present, usually located near the periphery of the tumors, but in some cases extending into the diffuse tumor tissue. Most of the tumors displayed variable immunohistochemical reactivity for cytokeratin, vimentin and neuron-specific enolase but were negative for muscle-specific actin or desmin except in the stromal tracts. Detailed examination of all available gastric tissue revealed the presence of additional microscopic neoplasms and precursor hyperplastic lesions. All of these were typical gastric neuroendocrine cell lesions (gastric carcinoids) originating in the fundic mucosa but occasionally invading submucosally, and consisting of epithelial cells in organized clusters, rosettes or primitive tubules. The enterochromaffin-like (ECL) nature of these microscopic neoplasms and precursor lesions was substantiated by strong immunohistochemical reactivity for cytokeratin, neuron-specific enolase and chromogranin A, and a negative reaction for vimentin. One microscopic tumor showed a transition from differentiated neuroendocrine type in the fundic mucosa to a dispersed "mesenchyme-like" pattern in the submucosal extension. An additional finding in the butachlor-treated male and female rats was atrophy of the fundic mucosa involving, in particular, reduction in the numbers of parietal cells. This effect was dose-related, being most severe in the high-dose (3000 ppm) females. On the basis of their morphological characteristics, coupled with the continuity evident in the microscopic lesions, it is concluded that the macroscopic stomach tumors associated with the dietary administration of butachlor are poorly differentiated gastric carcinoids, in some cases admixed with a non-neuroendocrine epithelial element. Fundic ECL and stem cells are known to be under the trophic influence of gastrin, which is apparently responsible for the induction of the tumors associated with butachlor administration. Gastric tumor development involving gastrin is recognized as a secondary, hormonal mechanism of carcinogenesis, demonstrating a dose-threshold phenomenon.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Identity and pathogenesis of stomach tumors in Sprague-Dawley rats associated with the dietary administration of butachlor. 758 Jan 13

Tenascin is a novel six-armed extracellular-matrix glycoprotein expressed in association with mesenchymal-epithelial interactions, and its expression is temporally and spatially restricted during organogenesis and carcinogenesis. The distribution and alterations in the expression of fibronectin, laminin, and especially of tenascin, were compared between in vitro and in vivo studies with rat epithelial (hepatocyte-derived) and nonepithelial (sarcoma-derived) cell lines. Immunoprecipitation studies revealed that the production of extracellular-matrix glycoproteins varied among the cell lines. Two ascites-hepatoma-derived cell lines and one sarcoma-derived line were found to synthesize tenascin in vitro. Their major tenascin isoform yielded a molecular weight of 220 kDa under reducing conditions. The other cell lines examined, including all of those derived from normal hepatocytes, were negative for the expression of tenascin. Coculture studies were performed between epithelial and nonepithelial cell lines. No drastic change in tenascin expression was found after coculturing the cells. As an in vivo study, cell lines were transplanted into nude mice. All xenografts of the epithelial lines were associated with a strong positive reaction for extracellular-matrix glycoproteins, and especially for tenascin, in the mouse fibrous stroma adjacent to them. This represents the epithelial induction of stromal tenascin. Whether or not they produced tenascin in vitro, after transplantation none of the epithelial cell lines themselves produced tenascin, whereas both of the nonepithelial cell lines prominently produced tenascin. These findings suggest that, in the process of interactions between epithelial and nonepithelial cells, the expression of tenascin depends on the switch from in vitro to in vivo.
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PMID:Tenascin expression in vitro and in vivo: comparison between epithelial and nonepithelial rat cell lines. 768 94

Metoclopramide (MCA), a N-substituted benzamide, causes DNA strand breaks and inhibits DNA repair in vitro and sensitizes radiation and chemotherapeutic drugs in human squamous cell carcinomas when xenographed into nude mice or in a rat glioma model. Here we report on the evaluation of the mechanism behind the radiosensitizing effects of MCA. DNA damage was measured in vivo in a CBA-mouse tumor line (A12B3, sarcoma tumor) by using both alkaline elution and nucleoid sedimentation analysis of cell suspensions prepared from either resected tumor, spleen tissues or whole blood samples. The amount of DNA damage caused by radiation alone, measured 30 min after the irradiation was started, was dose dependent up to 18 Gy in all tissues. The radiation-induced DNA damage in tumor tissue was elevated compared to radiation alone in the presence of MCA, but the level was not higher at 18 Gy compared to 6 Gy in the presence of MCA, and it was still not fully repaired 12 h after irradiation. HPLC analysis of the NAD pools in tumor tissue after DNA damage induction showed a delay in the recovery of the NAD pools (presumably due to the presence of still unrepaired DNA) after exposure to MCA (2 mg/kg) + radiation (6 Gy) compared to tumors exposed to radiation (6 Gy) only, which were fully restored after 48 h. These data confirm earlier published in vitro data on MCA as an inducer of DNA damage and an effector of DNA repair. In addition, the in vivo measurement of radiation-induced DNA damage and DNA repair using the nucleoid sedimentation and alkaline elution assays together with NAD pool determinations may prove to be effective intermediate endpoints in the evaluation of drugs as potential radiosensitizers.
Carcinogenesis 1995 May
PMID:In vivo tumor measurement of DNA damage, DNA repair and NAD pools as indicators of radiosensitization by metoclopramide. 776 61


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