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)

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

The metabolism of 7-methoxy-2-nitro-naphtho[2,1-b]furan and the subsequent binding to DNA, under aerobic conditions, were investigated using liver microsomes of both untreated rats and rats pre-treated with 3-methylcholanthrene [3-MC]. The metabolites were analyzed by HPLC. The following compounds: 7-hydroxy-2-nitro-naphtho[2,1-b]-furan-6,9-dione; 6,7-dihydro-2-nitro-naphtho[2,1-b]furan; 7-hydroxy-2-nitro-naphtho[2,1-b]furan and 6-hydroxy-7-methoxy-2-nitro-naphtho[2,1-b]furan have been identified by their UV-visible, mass spectra, NMR spectra and by comparison to an authentic reference sample. Qualitative and quantitative metabolic charts involving only ring oxidation have been established.
Carcinogenesis 1988 Nov
PMID:Oxidative metabolism of 7-methoxy-2-nitro-naphtho[2,1-b]furan (R 7000) by the microsomal system isolated from 3-methylcholanthrene-induced rat liver. 318 Mar 37

The tissue localization of epidermal growth factor receptor (EGF-R) in experimental squamous cell carcinoma of the mouse uterine cervix was examined immunohistochemically. Carcinoma was induced by the insertion of a 20-methylcholanthrene (MC)-impregnated thread into the cervical canal of the mouse. Tissue sections (of normal columnar epithelium, proliferation, atypical proliferation, early invasive carcinoma, invasive carcinoma and metastatic carcinoma) were stained by the avidin/biotin immunoperoxidase technique using anti-EGF-R monoclonal antibody. Normal columnar epithelium was negative for EGF-R, whereas proliferation was partly positive. The lesions of atypical proliferation and early invasive carcinoma had a positive staining for EGF-R. The staining for EGF-R declined in the lesion of invasive carcinoma. Metastatic carcinoma was not stained for EGF-R. These results suggest that EGF-R may play an important role in the early stage of carcinogenesis of the mouse uterine cervix induced by 20-MC.
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PMID:[Immunohistochemical studies on epidermal growth factor receptor in experimental squamous cell carcinoma of the uterine cervix of mice]. 322 81

Several different protease inhibitors have the ability to suppress transformation in vitro and carcinogenesis in vivo. The mechanism(s) by which protease inhibitors suppress carcinogenesis, however, is not fully understood. Presumably, these agents inhibit one or more intracellular proteases whose functions are essential for the induction and/or expression of the transformed phenotype. We have isolated an endopeptidase activity capable of hydrolyzing the substrate Boc-Val-Pro-Arg-MCA (Boc = butoxycarbonyl; MCA = 7-amino-4-methylcoumarin) from C3H/10T1/2 mouse embryo fibroblast cells. This intracellular protease was inhibited by the soybean-derived Bowman-Birk inhibitor (BBI), chymostatin, and L-1-tosylamido-2-phenylethyl chloromethyl ketone, all of which have anticarcinogenic activity, but was unaffected by soybean trypsin inhibitor, which lacks anticarcinogenic activity. Other protease inhibitors affected the proteolytic activity to an extent that correlates with their relative ability to suppress transformation in vitro. The enzyme has a mass of about 70 kDa, contains a single subunit, and exhibits maximal activity at pH 7.0. Diisopropyl fluorophosphate covalently binds to this enzyme and blocks its activity, indicating that the enzyme is a serine protease. We have previously demonstrated that several protease inhibitors are effective suppressors of radiation-induced transformation of C3H/10T1/2 cells. Since these agents reduce the Boc-Val-Pro-Arg-MCA-hydrolyzing activity to an extent that correlates with their ability to inhibit malignant transformation in vitro, this endopeptidase activity may be a cellular target of the anticarcinogenic protease inhibitors.
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PMID:A serine protease activity in C3H/10T1/2 cells that is inhibited by anticarcinogenic protease inhibitors. 329 74

Even AHH-inducible mouse strains vary in their susceptibilities to MCA sarcomagenesis. Previous work showed that the rank-order of strain susceptibility depended upon the dosage of MCA; the strain most susceptible to a high dose became the least susceptible to a low one and vice versa. We now confirm our previous findings and test the hypothesis that the reversal, with dosage, of the rank-order of relative strain-susceptibility has an immunological basis. This was tested in two ways: by examining the effect of immunosuppression on strain-susceptibility to sarcomagenesis and by transplanting parental bone marrow into irradiated F1 hybrid to see if the relative MCA-susceptibility characteristics of the parental donors could be transferred. The results of both studies suggest that the rank-order-reversal phenomenon is caused, at least in part, by differences in the immunological reactivities of the strains. Inasmuch as immunosuppression inhibited the response of the C3 mice to a high dose of carcinogen, but facilitated carcinogenesis among the B6, the level of innate immune capacity most conducive to high-dose carcinogenesis is apparently intermediate between the levels of these two strains.
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PMID:The immune basis of dosage-induced reversal of the rank-order of strain susceptibility to MCA. 354 44

Wistar rats were injected with the carcinogen 3-MC. The effect of psychoactive drugs on tumor-bearing rats was examined with respect to tumor growth, survival time, and remissions. CNS drugs were given both prophylactically and therapeutically. Psychopharmaceuticals like piracetam and pyrithioxin as well as catecholamine-agonists like imipramine had a definite antineoplastic effect. This effect was increased when combined with other CNS drugs and, in particular, the combination of piracetam with chemotherapeutic agents resulted in a high rate of remission and reduced the toxicity of chemotherapy. Surgical removal of tumors and subsequent treatment with CNS drugs led to a high rate of cure without metastasis. After tumor appearance, we found cerebral neuropathological changes as described in the paraneoplastic syndrome. The EEGs of 3-MC-injected rats showed early pathognomic changes in frequency and amplitude. Similar changes were found in animals with transplantation tumors (Walker carcinoma and Jensen sarcoma). The EEG pattern was normalized after surgical removal of Jensen sarcoma and treatment with piracetam and pyrithioxin. These EEG changes might have occurred as a result of transmitter metabolism; ie, carcinogenesis of both induced tumors and transplanted tumors was accompanied by an increase of GABA content in hypothalamus and hippocampus and a reduced concentration of monoamines or their metabolites in hypothalamus and caudate nucleus. Long-term treatment with piracetam or imipramine again arrested all these changes. More recently, we achieved good results with the combination of CNS drugs and cAMP agonists. We therefore conclude that carcinogenesis interferes with the metabolism or availability of cyclic nucleotides and transmitters that regulate their level. CNS drugs may effect a new balance resulting in tumor suppression.
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PMID:Carcinogenesis and the central nervous system. 374 5

The biological activities in vitro of the incomplete (second-stage) tumor promoter, 12-O-retinoyl phorbol-13-acetate (RPA), and the complete tumor promoter, 12-O-tetradecanoyl phorbol-13-acetate (TPA) were compared. The doses of TPA and RPA necessary to inhibit the specific binding of [3H]-phorbol-12,13-dibutyrate ([3H]PDBu) to BALB/c 3T3 cells (50% inhibition doses; ID50; 8-13 ng/ml) were very similar; however, RPA was less potent than TPA in inhibiting [3H]-PDBu binding to Friend erythroleukemia cells (FELC). Intercellular communication between BALB/c 3T3 cells, measured by transfer of microinjected fluorescent dye (Lucifer Yellow), was inhibited by RPA as well as by TPA; TPA was about five times more potent than RPA. RPA also inhibited FELC differentiation induced by hexamethylene bisacetamide (HMBA) but not the differentiation of a TPA-resistant clone. The dose-responses of these two compounds in inhibiting differentiation of both TPA-sensitive and resistant FELC were very similar. When TPA and RPA were compared in their promoting activity of in vitro cell transformation of BALB/c 3T3 cells initiated with 3-methylcholanthrene (MCA, 0.1 microgram/ml), both TPA and RPA significantly increased the yield of morphologically transformed foci, and RPA was approximately 10 times more potent than TPA. These results suggest that RPA and TPA share many common in vitro biological effects and that these in vitro studies do not allow us to delineate clearly the effect of a second-stage tumor promoter from that of complete tumor promoters such as TPA.
Carcinogenesis 1985 Aug
PMID:Comparative effects of a complete tumor promoter, TPA, and a second-stage tumor promoter, RPA, on intercellular communication, cell differentiation and cell transformation. 386 Mar 6

The transformation of C3H/10T1/2 cells can be made to proceed through discrete stages of initiation and promotion. Studies of the effect of cell density upon focus formation in cultures treated with MNNG and TPA suggest that initiation by MNNG is due to a relatively infrequent, irreversible event induced by a single carcinogen treatment. In contrast, promotion appears to be a reversible process requiring multiple treatments with TPA over a protracted period of time. Some evidence suggests that promotion may entail the induction of phenotypic changes which impart a growth advantage to phenotypically unstable "initiated" cell populations. The actual cellular mechanism(s) for most of the phenomena observed in C3H/10T1/2 cultures have eluded precise definition and widely divergent hypotheses have been advanced to explain transformation, initiation, and promotion. Conceivably there are multiple mechanisms responsible for each of these phenomenon. Some agents may transform by a multistage mechanism whereas others may exert their effects in a more direct fashion. Some of the foci produced by promotion may be the result of simple selective processes, others the product of more complex inductive events. Variations would thus be expected between laboratories working with different protocols and agents. As demonstrated by the possible involvement of an MCA residue in transformation, it is also apparent that fundamental technical aspects of this conceptually simple cell transformation system are poorly understood. While it is natural to develop mechanistic models based on quantitative observations of transformation, a limited understanding of the basic cell culture variables which modulate both the induction and expression of transformation dictate that caution be exercised in extrapolating the significance of such models to in vivo carcinogenesis.
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PMID:Mechanistic aspects of initiation and promotion in C3H/10T1/2 cells. 405 71

3-Methylcholanthrene (3MC) administered p.o. has induced tumors of the hamster gastrointestinal tract (GIT), including the large intestine. This process may depend on the concentration of unchanged hydrocarbon in the GIT contents. Benzo(a)pyrene (BP) ingestion could be involved in human GIT carcinogenesis. Accordingly, male Syrian golden hamsters were fed diets containing BP or 3MC for 10 days. Feces collected during the last two to three days of feeding were analyzed for the unchanged hydrocarbons by KOH:methanol digestion, Florisil column and paper chromatography, and ultraviolet spectrophotometry. With a semisynthetic diet containing 5% Alphacel, 6% corn oil, and 100 microgram BP per g. fecal BP excretion was 0.45% of the dose. Variation of the corn oil content had little effect. Fecal BP excretion was increased 13 times (to 6% of the dose) when 5% wheat brain was used in place of Alphacel and 4.5 times when a commercial diet was used. This suggests that bran adsorbed or sequestered the BP. Water content of the large-intestine contents was increased when the brain diet was fed. Both these factors could affect mucosal exposure to BP. For 3MC, fecal excretion of unchanged hydrocarbon was 14 times greater than for BP under similar conditions. The GIT contents of hamsters fed BP or 3MC showed hydrocarbon concentrations in the order: stomach greater than lower large intestine greater than other sections.
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PMID:Effect of diet on fecal excretion and gastrointestinal tract distribution of unmetabolized benzo(a)pyrene and 3- methylcholanthrene when these compounds are administered orally to hamsters. 626 63

When benzo(a)pyrene was used to evaluate the transformability of 129 hamster embryo cell preparations from pooled or individual embryos, approximately 50% of the cultures were transformable. A transformable and a non-transformable cell culture were further tested with other carcinogens (3-methylcholanthrene [MCA], benzyl chloride, ethyl-p-toluenesulfonate, 2-naphthylamine, and aflatoxin B1). The transformable culture responded to all of the carcinogens while the non-transformable culture always gave negative results. Aryl hydrocarbon hydroxylase (AHH) and epoxide hydrase (EH) levels were compared in the two cell cultures using beta-naphthoflavone (BNF), benz(a)anthracene (BA), sodium phenobarbital (PB) or MCA as microsomal enzyme-inducing agents. It was found that AHH levels and the degree of induction following treatment of the cells with BNF or BA were consistently higher in the transformable than in the non-transformable cells following treatment with either BNF, BA, PB or MCA. Inducible AHH and EH levels might, therefore, be useful as predictors of the transformation potential of hamster embryo cell cultures.
Carcinogenesis 1980 Apr
PMID:Correlation between transformation potential and inducible enzyme levels of hamster embryo cells. 626 16


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