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

Interferons potentiate the cytotoxic effects of certain antineoplastic drugs on human tumor cells both in vitro and in vivo, although the mechanism of interferon's synergistic action is unknown. Interferon may act by modulating the expression of DNA repair activity in cells. To test this hypothesis, we maintained parallel cultures of normal O6-methylguanine repair-proficient human fibroblasts and tumor cells, or RSV-and SV40-transformed repair-deficient Mer- human fibroblasts in medium containing 0, 100, 500 or 680 U/ml human interferon alpha or beta; after 1-10 weeks, cultures were challenged with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, CAS: 70-25-7) and assayed for colony-forming ability. Based on the dose at 99% lethality, MNNG cytotoxicity was potentiated from 1.3- to 9-fold in interferon-treated cultures, compared with control cultures (no interferon). A significant potentiation was observed both with Mer+ normal fibroblasts (KD strain) and tumor cells (HOS) and with Mer- SV40-transformed fibroblasts (IMR90-830 and GM638) as well as with RSV-transformed cells (RHOS). However, the degree of potentiation was greater in Mer- virus-transformed cells than in Mer+ cells. The greatest effects were observed with Mer- IMR90-830 cells (5- to 9-fold reduction of dose at 99% lethality). Therefore, because the Mer+ phenotype is not required in order for HuIFNs to sensitize cells to killing by MNNG, interferon does not act by modulating O6-methylguanine repair. However, the effect of interferon on O6-methylguanine-DNA methyltransferase levels and on DNA excision repair should be examined in future experiments.
Carcinogenesis 1989 Feb
PMID:Synergistic killing of virus-transformed human cells with interferon and N-methyl-N'-nitro-N-nitrosoguanidine. 246 81

There seems to be a current view that the inhibition of DNA methylation may be a mechanism of initiation of carcinogenesis or one of the steps required in the carcinogenic process. However, because of the deficiencies in research works on cellular level, there is a long way to make such a general relationship between carcinogen and the inhibition of cellular DNA methylation. In this paper the effects of some chemical carcinogens on methylation of newly replicated DNA in human FL cells was analyzed by comparing the weight average length (Lw) of the DNA digests after complete digestion by restriction endonuclease Hpa II. It was observed that two non-genotoxic carcinogens (5-azacytidine and L-ethionine) and two genotoxic carcinogens (MNNG and aflatoxin B1) used in this study all caused obvious cytotoxicity on FL cells at the test concentration. Five days after the termination of 5-azacytidine treatment (2 x 10(-6) M, 24 hours), Lw (kb) of the Hpa II digests of cellular DNA was smaller than that of control (8.0 +/- 0.1 vs 10.9 +/- 1.0, P less than 0.01), the Lw change rate was -27%. When DNA was analyzed from FL cells after 9 days continuous treatment of L-ethionine (2 x 10 M), the digestibility of Hpa II was also increased as compared with that of the control, the Lw values (kb) showed a decrease of about 8% (9.8 +/- 0.3 vs 10.6 +/- 0.3, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Is hypomethylation of cellular DNA a step required in the initiation process of chemical carcinogenesis?]. 248 41

Six natural foods were tested with Ames Test for their anti-mutagenic effect on 2-AF, AFTB, MNNG, NaN3 induced mutagenic activity in TA99 and TA100. The tested substances were extracted repeatedly with acetone. The revertants induced by 2-AF AFTB1 (with TA98, TA100). MNNG (with TA100) were significantly decreased when the six natural foods were added to the medium. The results revealed that all six natural foods showed remarkable inhibitory effect on 2-AF, AFTB1, MNNG induced mutagenic activity for strains TA98 and TA100 and suggested the presence of anti-mutagenic substances in the six natural foods. This experiment provides a scientific basis to the study of food substances for the prevention of carcinogenesis. It is considered that the six natural foods possess remarkable anti-mutagenic effect and is practically valuable in the field of chemoprophylaxis of Cancer in men.
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PMID:[Research on the anti-mutagenic effect of six natural foods]. 258 25

The promoting effect of bile acids in physiological concentration in colon carcinogenesis was studied using male Wistar rats with defunctioned colon. After an instillation of MNNG, collected rat faces (group A), secondary bile acids i.e. deoxycholic acid and lithocholic acid in equal concentration to rat feces (group B) and control material (group C) was instilled in the defunctioned colon. Concerning the incidence and the number of macroscopically visible tumor, no significant difference was found among these three groups. However, the number of histological lesion with atypia in flat mucosa of the colon in group A and B was significantly greater than that in group C. Considering this result and the results obtained from prestudy of kinetics of colonic epithelial cells by the use of anti BrdU monoclonal antibody, feces and physiological concentration of bile acids had a promoting effect in colon carcinogenesis.
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PMID:[The role of bile acids with physiological concentration in colon carcinogenesis]. 258 88

Efforts to investigate the progression of events that lead human cells of epithelial origin to become neoplastic in response to carcinogenic agents have been aided by the development of tissue culture systems for propagation of epithelial cells. We have recently developed an in vitro multistep model suitable for the study of human epithelial cell carcinogenesis. Primary human epidermal keratinocytes acquired indefinite lifespan in culture but did not undergo malignant conversion in response to infection with Adl2-SV40 virus. Subsequent addition of Ki-MSV, which contains a K-ras oncogene, to these cells induced morphological alterations and the acquisition of neoplastic properties. Nontumorigenic human epidermal keratinocytes immortalized by Adl2-SV40 virus (RHEK-1) were also transformed by treatment with chemical carcinogens (MNNG or 4NQO) and by X-ray irradiation. Such transformants showed morphological alterations and induced carcinomas when transplanted into nude mice. This in vitro system may be useful in assessing environmental carcinogens for human epithelial cells and in detecting new human oncogenes since ras oncogenes were not activated in these chemical--or X-ray--transformed RHEK-1 lines. Subsequently, it was found that this line could be transformed neoplastically by a variety of retroviruses containing H-ras, bas, fes, fms, erbB and src oncogenes. In addition, our recent results indicate that nontumorigenic RHEK-1 cells can be transformed following transfection with an activated human oncogene. Thus, this in vitro system may be useful in studying the interaction of a variety of carcinogenic agents and human epithelial cells. These findings demonstrate the malignant transformation of human primary epithelial cells in culture by the combined action of tumor viruses and chemical carcinogens or X-ray irradiation and support a multistep process for neoplastic conversion. Further, evidence for the multistep nature of neoplastic transformation of human epithelial cells in vitro using other model systems is presented.
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PMID:Neoplastic transformation of human epithelial cells in vitro. 268 34

The present studies intend to heighten the sensitivity of BALB/3T3 cells to chemical carcinogens in a transformation assay, by including exposure of carcinogen-treated cells to a tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA). In the assay, cells were first treated with a known or suspected carcinogen for 72 h, cultured in normal medium for 3 days, exposed to media with and without TPA for 2 weeks, and cultured in normal medium for an additional 3 weeks. Benzo[a]pyrene, a potent carcinogen with a polycyclic aromatic hydrocarbon structure, caused transformation in the presence and absence of TPA. N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG), a carcinogen with direct-acting alkylating ability, did not induce significant transformation without TPA, while treatment with MNNG followed by TPA produced numerous transformed foci, classifying MNNG as an initiating agent of transformation under the condition presented in this report. 3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide (AF-2), sodium nitrite and butylated hydroxyanisole (BHA), which are carcinogenic and/or mutagenic, produced transformed foci in significant numbers of treated dishes in the presence but not in the absence of TPA. Butylated hydroxytoluene (BHT) and sodium saccharin, which are considered to be a modifier and a promoter of carcinogenesis, did not cause significant transformation with or without TPA treatment. These studies suggest that this 2-stage transformation system is capable of detecting a wider range of chemical carcinogens as initiating agents than the standard assay. Studies on the transformation assay schedule revealed that the proportion of dishes with foci, the number of foci per dish and sizes of foci all increased in the normal medium after the termination of TPA treatment. Therefore, transformed cells appear to proliferate independently of TPA after those cells are released by TPA from postconfluence inhibition of cell division.
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PMID:Improvement of carcinogen identification in BALB/3T3 cell transformation by application of a 2-stage method. 279 27

The influence of bile acids on the development of remnant gastric carcinoma was examined by investigating the incidence of carcinogenesis in noninbred male Wistar rats treated orally with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG; CAS 70-25-7; 1-methyl-3-nitro-1-nitrosoguanidine) and fed a diet containing 1% cholesterol. The high-cholesterol diet did not influence the incidence of carcinoma in the nongastrectomized, MNNG-treated groups of rats. However, in the gastrectomized groups, the incidence of carcinoma was significantly higher in the group given the high-cholesterol diet (60.6%) than in the group given a normal diet (35.5%). Histologically undifferentiated adenocarcinoma was recognized more frequently in the high-cholesterol-diet group. Three gastrectomized rats not treated with MNNG but fed the high-cholesterol diet developed remnant gastric carcinoma (13%), whereas none of the rats given the normal diet did. Because the fecal excretion of bile acids increased significantly in the rats fed the high-cholesterol diet and the gastroduodenal reflux of bile acids was probably accelerated, the increase in the incidence of carcinogenesis in the remnant stomach was considered to be the result of the increase in the reflux of bile acids evoked by a high-cholesterol diet.
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PMID:Enhanced induction by high-cholesterol diet of remnant gastric carcinogenesis by N-methyl-N'-nitro-N-nitrosoguanidine in rats. 290 53

Inhibition of poly(ADP-Rib) by benzamide (BA) or 3-amino-benzamide (3AB) for a limited period (i.e., when ADP-ribosylation is elevated) during and shortly following X-ray or MNNG-induced DNA damage of BALB/3T3 cells significantly (3- to 30-fold) enhanced transformation frequency by these agents. Individual Type III foci isolated from benzamide, X-ray, or X-ray plus benzamide treated cultures were established and characterized for growth in soft agar and for tumor induction in nude mice. DNA isolated from representative transformed lines established as a result of BA, X-ray or X-ray and BA treatments was transfected onto NIH/3T3 cells. Transformation efficiencies ranging from 0.17 to 0.28 foci/micrograms of DNA were observed suggesting the possibility that dominant transforming gene(s) were responsible for the oncogenic phenotype of radiation and benzamide transformed DNA.
Carcinogenesis 1986 Feb
PMID:Relationship between DNA strand breaks and inhibition of poly (ADP-ribosylation): enhancement of carcinogen-induced transformation. 308 Dec 74

Retinoic acid has been reported to act as an inhibitor and as an enhancer of mouse skin carcinogenesis in vivo. However, no in vitro cell transformation model has been reported to be sensitive to both effects. In an attempt to provide such a model, the effect of retinoic acid on an early step in carcinogen-induced transformation of mouse epidermal cell line 271c was measured using a recently described assay. The step observed is altered response to extracellular Ca2+ as an epidermal terminal differentiation signal. In six out of twelve experiments retinoic acid increased the frequency of altered colonies resulting from treatment with three chemical carcinogens. The enhancement effect was stronger after DMBA treatment than MNNG or MCA, resulting in up to a 13.7-fold increase in the frequency of colonies exhibiting altered terminal differentiation (TF). On the other hand, up to a 10-fold decrease in TF was observed in other experiments. Both the enhancement and inhibitory effects were greater at the higher doses of retinoic acid tested in the range of 10(-10) - 10(-7) M. Variations in cloning efficiency or surviving colony density did not account for the effects on TF. Enhancement effects tended to be observed at lower doses of carcinogen, or in experiments in which TF resulting from treatment with carcinogen alone was in the lower range observed. However, the factors determining each effect have yet to be defined. The enhancement effect of retinoic acid was not merely suppression of the phenotypic endpoint of the in vitro assays, because treatment of carcinogen-altered cells with retinoic acid or TPA in vitro also enhanced their tumorigenicity in vivo compared to acetone controls. These findings suggest that studies of the determinants of retinoid activity should be a prerequisite to their use in chemoprevention.
Carcinogenesis 1986 Sep
PMID:Retinoic acid enhancement of an early step in the transformation of mouse epidermal cells in vitro. 309 Dec 82

Extrapolation from rodent genotoxicity data to humans is complicated by variables such as interspecies differences in carcinogen metabolism and DNA repair. A xenograft system containing human bronchial epithelial cells was used to assess the induction of unscheduled DNA synthesis (UDS) by carcinogens and to compare the response with that of rat tracheal epithelium. Cells from human bronchus were grown in explant culture, inoculated into de-epithelialized rat tracheas and implanted subcutaneously into nude mice. Within six weeks, a differentiated mucociliary epithelium lined the xenografted tracheas. Fresh rat tracheas and human xenografts were cut into rings and incubated in media containing [3H]thymidine and either the direct-acting carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, 3-1000 microM), or a carcinogen requiring metabolic activation, 4-nitroquinoline-1-oxide (4-NQO, 3-100 microM). Tissues were then fixed, sectioned, processed for autoradiography and the number of nuclear grains (NG) determined for 100 epithelial cells lining the trachea in each section. A time- and concentration-dependent increase in NG was observed in both human xenografts and rat tracheas after treatment with MNNG or 4-NQO, indicating induction of UDS by these agents. The UDS response to MNNG in the human xenografts was similar to that observed in the rat tracheas, whereas the response to 4-NQO was greater in rat tracheas. These studies indicate that the human xenograft system should have applications for the study of carcinogen-induced damage in normal bronchial epithelial cells.
Carcinogenesis 1988 Mar
PMID:Carcinogen-induced unscheduled DNA synthesis in xenotransplanted human tracheobronchial epithelium: comparison with rat tracheal epithelium. 312 97


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