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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cells of the human lymphoblastoid non-producer line Raji were cloned in soft agar. Individual colonies were isolated and analyzed for their inducibility of the Epstein-Barr virus-associated early antigen (EA). The induction of EA by the tumor promoter TPA varied among the different cell clones. Clones with very high and very low inducibility of the resident Epstein-Barr virus genome were further analyzed. Constant differences in the inducibility of EA were observed after activation by tumor promoters, 5-iododeoxyuridine or antibodies to human IgM. Induction of EA synthesis by superinfection with Epstein-Barr virus from the P3HR-1 line, however, did not vary among the clones tested. No differences in expression of the Epstein-Barr virus-associated nuclear antigen (EBNA) were noted in cells of clones with high or low susceptibility to EA induction. DNA reassociation kinetics demonstrated that Raji cells with high susceptibility to EA induction contained a significantly higher number of Epstein-Barr virus genome equivalents per cell than cells with low susceptibility. Treatment of Raji cells with the tumor promoter TPA did not change the ratio of Epstein-Barr virus-specific DNA to cellular DNA.
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PMID:Differential inducibility of Epstein-Barr virus in cloned, non-producer Raji cells. 8

Release of prostaglandin E2 (PGE2) in cultured peritoneal macrophages of NMRI mice by skin irritant tumor initiators and promoters was investigated. Initiators of the polycyclic aromatic hydrocarbon type, e.g., DMBA, caused slight irritation on the mouse ear but even relatively high doses did not stimulate PGE2-release to any measurable extent within 4 h after administration in vitro. Apparently there is no correlation between irritation and initiating activity in mouse skin and PGE2-release in macrophages. On the other hand, promoters of the diterpene ester type, e.g., TPA, were strong irritants on the mouse ear. Even low doses of these compounds stimulated PGE2-release from macrophages dramatically within 1 h after administration in vitro. Moreover, a good correlation was established between irritant and promoting activity in mouse skin and PGE2-release in macrophages of a series of tigliane, ingenane and daphnane type diterpene derivatives. These results suggest that also in mouse skin PGE2-release may occur following exposure of the target cells to promoters of the diterpene ester type resembling one of the most early molecular events of promotion. This event could initiate both skin irritation and cell proliferation.
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PMID:Inflammatory, tumor initiating and promoting activities of polycyclic aromatic hydrocarbons and diterpene esters in mouse skin as compared with their prostaglandin releasing potency in vitro. 9 35

The classical 2-stage carcinogenesis experiment has been modified in that the carcinogen DMBA was applied to pregnant mother animals at different dose levels and different time intervals during pregnancy. Promotion with the phorbol ester TPA was performed as usual by application of the promoter on the back skin of mice of the F-1 generation. It can be shown that it is possible to initiate fetal epidermal cells by transmaternal route and to promote them to produce visible skin tumors post natum. Tumor promotion by TPA is not restricted to the epidermis, since a broad spectrum of tumors of internal organs can be demonstrated in the initiated and promoted animals. This more general promoting activity of TPA--which implies its absorption and distribution throughout the whole body--has not yet been described. In addition, especially sensitive phases during fetal life with regard to initiation of cells by the carcinogen can be demonstrated. These phases comprise the last third of pregnancy and coincide with a high proliferative activity and the onset of differentiation of the fetal epidermis. The results emphasize the important role of prenatal carcinogenesis and demonstrate the increased risk also to the human organism by either prenatal initiation or postnatal promotion.
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PMID:Transmaternal modification of the Berenblum/Mottram experiment in mice. 10 83

Skin autografting or a single painting with the cocarcinogen TPA was used to induce epidermal hyperplasia in the back skin of C3H mice. Initiation by intragastric application of the carcinogen DMBA during this state of hyperplasia and subsequent promotion by repeated application of the cocarcinogen TPA led to decreased papilloma-formation, as compared to mice of a control group which had not been pretreated before initiation. Reports by others referring to increased susceptibility of replicating epidermal cells to the effect of initiation thus cannot be confirmed. The reduction of papilloma-formation can most probably be ascribed to effects of local inflammation, either preferentially but unspecifically damaging initiated cells, or facilitating a specific immune response against tumor-associated transplantation antigens of prospective tumor cells.
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PMID:[Skin transplantation in the study of chemical carcinogenesis. III. Reduced papilloma-formation after initiation during epidermal hyperplasia induced by skin grafting or by a single application of the cocarcinogen TPA]. 12 47

Histochemical activity of acid DNAse, intensity of nucleic acid staining and histological alterations in mouse interfollicular epidermis (I.F.E.) were investigated after a single dose or after chronic topical administration of two hyperplastic agents, of which one (croton oil) was a potent tumor promotor, and the other one (podophyllin) did not promote skin carcinogenesis. Podophyllin induced intense uniform I.F.E. hyperplasia without any proliferation of poorly differentiated basal cells, without increased nucleic acid staining and without any appreciably decreased acid DNAse activity. On the other hand, croton oil (as well as TPA) produced almost immediate, distinct hyperplasia of poorly differentiated basal cells with increased intensity in the staining of both nucleic acids and nearly complete deficiency in acid DNAse activity. Similar histochemical and histological patterns were observed at the sites of wounding hyperplasia in untreated control mice. Such wounding hyperplasia was thought also to be a tumor promoting factor. It was suggested that the decrease in acid DNAse activity which occurred almost immediately after administration of potent tumor promoters and which could not be induced by a hyperplastic agent without tumor promoting action may have a particular importance in the mechanisms of tumor promotion.
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PMID:Induction of the deficient acid DNAse activity in mouse interfollicular epidermis by croton oil as a possible tumor promoting mechanism. 14 59

Ether-permeabilized (nucleotide-permeable) Escherichia coli cells exhibited DNA excision repair when exposed to the following carcinogenic K-region epoxides: 7-methyl- and 7,12-dimethyl-benz[a]anthracene-5,6-oxide, chrysene-5,6-oxide and benzo[a]pyrene-4,5-oxide. This DNA excision repair was missing in uvr A and uvr B mutant cells. The K-region epoxide phenanthrene-9,10-oxide was ineffective in all E. coli strains tested. In contrast to the K-region epoxides which where found active only in wild type cells, 1,2,3,4-diepoxybutane and the 6,7-epoxides of the tumor promoter TPA (12-O-tetradecanoyl-phorbol-13-acetate) elicited DNA repair in uvrA, uvrB mutant cells as well. Enzymic activities catalyzing particular repair steps were identified by determining a) repair polymerization and b) size reduction of denatured DNA. A) An easily quantifiable effect in E. coli wild type cells was epoxide-induced repair polymerization. None of the K-region epoxides tested stimulated DNA repair synthesis in uvrA, uvrB mutant cells, indicating that the uvrA-, uvrB-controlled UV-endonuclease initiated excision repair by cleaving epoxide-damaged DNA. 1,2,3,4-Diepoxybutane and the TPA-6,7-oxides induced DNA repair polymerization in uvr-deficient cells, although to a lesser extent than in wild type cells, suggesting the involvement of uvr-independent incision steps. None of the epoxides induced repair polymerization in a mutant (polA107) lacking the 5'--3'exonucleolytic activity of DNA polymerase I (exonuclease VI). The absence of any repair polymerization in the polA107 mutant indicates that the exonuclease VI plays a central role in removing epoxide-damaged nucleotides. As evidenced by greatly reduced levels of repair polymerization measured in polA1 cells, DNA polymerase I was the main polymerizing enzyme. b) As a consequence of treatment with 7-methyl-benz[a]anthracene-5,6-oxide, DNA from wild type cells, contrary to uvrA mutant cells, showed size reduction after denaturation and sedimentation in alkaline sucrose gradients. This is explained by repair-specific endonucleolytic cleavage of damaged DNA. The incision required the presence of ATP indicating that functional UV-endonuclease needs ATP as a cofactor.
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PMID:Carcinogen-induced DNA repair in nucleotide-permeable Escherichia coli cells. Analysis of DNA repair induced by carcinogenic K-region epoxides and 1,2,3,4-diepoxybutane. 15 97

Ether-permeabilized (nucleotide-permeable) Escherichia coli cells respond to alkylating and arylalkylating carcinogens with DNA excision repair, as assessed by their stimulation of DNA repair synthesis. In the present work, we have investigated whether DNA repair synthesis in ether-treated E. coli cells can serve as a general indicator to monitor the DNA-binding of carcinogens, mutagens and antitumor agents. Therefore, a standard assay was developed and comparative analyses were performed on 11 ultimate carcinogens, 10 proximate carcinogens, 2 tumor promoters, 6 mutagens, and 12 antitumor agents. All ultimate carcinogens (alkylating, acylating, arylalkylating agents) and mutagens (e.g., hydrogeen peroxide, acridine derivatives) caused DNA excision repair in wild type cells as measured by [3H] dTMP incorporation and simultaneously inhibited replicative DNA synthesis to various extents. Control experiments with the mutant cells uvrA and uvrB were performed to determine whether the pyrimidine-dimer-specific UV-endonuclease was involved in the removal of DNA damage. This was found to be true for the ultimate carcinogens (Ac)2 ONFln, mitomycin C, and for very reactive alkylating carcinogens. None of the ultimate carcinogens induced repair polymerization in mutant cells lacking the 5'-3' exonucleolytic activity of DNA polymerase I. Proximate carcinogens, such as Me2NNO, 4-nitroquinoline-1-oxide and aflatoxins, did not induce excision repair in the standard assay, probably because of the inability of E. coli to perform the activation steps necessary for covalent DNA-binding. However, Me2NNO, when pretreated with Udenfriend's hydroxylating mixture, gave rise to a low level of repair polymerization in ether-treated cells. Intercalating mutagens, such as quinacrine and ethidum bromide, inhibited replicative DNA synthesis. However, they were not found to be repair-inducers. THE TUMOR PROMOters TPA and phorbol-12,13-didecanoate did not cause excision repair, even when applied at high concentrations, nor did they inhibit repair synthesis stimulated by MeNOUr or (Ac)2 ONFln. The antitumor agents may be classified into two groups on the basis of the influence they exert on DNA synthesis: members of the first group (involving BCNU and bleomycin) stimulate repair polymerization and, in addition, inhibit DNA replication. These compounds are known to bind covalently to DNA. The second group of drugs (including adriamycin and cis-Pt(II)diammine complexes) inhibits DNA replication without stimulating repair synthesis. The predominant DNA-interaction of these compounds is known to be a non-covalent (i.e., intercalative, electrostatic) binding. Our experiments show that the ether-permeabilized E. coli cell can be successfully used to test ultimate carcinogens, mutagens and antitumor agents for repair-inducing and replication-inhibiting activity. The standard test might be extended to pre- and proximate carcinogens, provided these can be suitably activated.
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PMID:The nucleotide-permeable Escherichia coli cell, a sensitive DNA repair indicator for carcinogens, mutagens, and antitumor agents binding covalently to DNA. 15 98

Cells of the Raji and NC37 lines can be induced by chemical inducers, such as BrdUrd and IdUrd, or the tumor-promoter TPA to EA-expression only, but do not reveal any VCA synthesis. After superinfection by nontransforming P3HR-1 EBV, however, a varying percentage of the cell population shows VCA synthesis and releases infectious viral particles. The recovered virus differs biologically from P3HR-1 EBV since it transforms human umbilical cord blood lymphocytes into EBNA-positive lymphoblastoid cell lines. Cells of these established lines are susceptible to renewed infection by P3HR-1 EBV which results in EA induction and VCA synthesis. Only cells of one line, NC37-R1, spontaneously produce VCA and EBV particles, which reveal transforming properties and do not induce EA upon superinfection of Raji cells. Infection of P3HR-1 EBV-converted BJA-B cells also leads to EA and VCA induction and the release of viral particles. In contrast to particles recovered from Raji and NC37 cells, no transforming activity was detectable in these virus preparations. According to these data, we propose that viral genomes persisting within Raji and NC37 cells are defective and become complemented by the superinfecting P3HR-1 virus.
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PMID:Recovery of transforming EBV from non-producer cells after superinfection with non-transforming P3HR-1 EBV. 21 77

TPA, a highly active tumor-promoting agent, is an effective mitogen for primate peripheral blood lymphocytes. Optimal stimulation of human lymphocytes was obtained 4 days after the addition of TPA at a concentration of 7.5 ng/ml. Lymphocyte fractionation experiments demonstrated that both T and B cells incorporated 3H-thymidine significantly in response to TPA. Lymphocyte blastogenesis was not due to the reactivation of latent herpesviruses by the tumor promoter, since similar responses to TPA were obtained with virus-genome positive or negative cells. Increased levels of DNA synthesis were observed when TPA was added to marmoset, baboon, rhesus monkey, or chimpanzee peripheral blood lymphocytes. Canine peripheral blood lymphocytes and spleen cells from guinea pigs, rats, and mice were not stimulated by TPA. These observations suggest that TPA-induced lymphocyte blastogenesis may be useful for studies of lymphocyte activation and of the molecular mechanisms of action of tumor-promoting phorbol esters.
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PMID:Lymphocyte activation by the tumor-promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA). 22 78

Hypotheses are presented of the detailed molecular structure of two prostaglandin receptors both concerned in tumor-promotion processes. These structures have been derived by the comparison of the molecular structure of agents active at the site with (i) a simple theoretical protein structure and (ii) the known x-ray structure of phospholipase A2. The first model receptor is stimulatory to the tumor-promotion process and may be located on the control system for ornithine decarboxylase. The binding of PG here is cooperative with the binding of Ca++. Naturally-occurring agonists at this receptor may include members of the cathartic class of drugs such as colocynth, chrysarobin, etc. Naturally-occurring antagonists at this site may include a number of anti-tumor compounds such as datiscoside. The second model receptor (PGE1) is inhibitory to the tumor-promotion process and is located at a specific allosteric site on the x-ray-determined structure of phospholipase A2. This site overlaps for one for lysolecithin (excitatory), for which tumor-promoting phorbol esters such as TPA are agonists and some anti-tumor drugs such as maytansine may be antagonists.
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PMID:On the molecular structure of some prostaglandin receptors. 23 33


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