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

The effects of N-(4-hydroxyphenyl)retinamide (4-HPR) and all-trans-retinoic acid (tRA) on the exogenous and endogenous models of rat liver carcinogenesis respectively using diethylnitrosamine (DEN) and a choline-deficient, L-amino acid-defined (CDAA) diet were studied. For the exogenous study, male Fischer 344 rats, 6 weeks old, were given a single i.p. dose of 200 mg/kg body wt of DEN, partially hepatectomized at week 3, administered 4-HPR at doses of 0, 0.04, 0.08 and 0.16% or tRA at 0, 0.004, 0.008 and 0.015% in diet from week 2 for 6 weeks, and killed at the end of week 8. For the endogenous study, rats were fed the CDAA diet containing 4-HPR or tRA for 12 weeks and killed at the end of week 12. 4-HPR decreased the numbers and sizes of the glutathione S-transferase placental form-positive foci, assayed as putative preneoplastic lesions, the levels of 8-hydroxyguanine (8-OHG), a parameter of oxidative DNA damage, and the bromodeoxyuridine labeling indices (BrdU L.I.) by all three doses in the DEN-initiated case and, more prominently, in the CDAA diet-associated case. In contrast, while tRA failed to exert inhibitory effects apparently on foci development, 8-OHG formation or BrdU labeling in the DEN-initiated case, it reduced the numbers and sizes of the foci, the 8-OHG levels and the BrdU L.I. by all three doses in the CDAA diet-associated case. Furthermore, both 4-HPR and tRA inhibited the CDAA diet-associated induction of hepatocyte necrosis and connective tissue increase but not intrahepatocellular fat accumulation. These results indicate that 4-HPR exerts chemopreventive effects against the exogenous and endogenous rat liver carcinogenesis, while tRA can inhibit only the latter.
Carcinogenesis 1997 Nov
PMID:Inhibition by N-(4-hydroxyphenyl)retinamide and all-trans-retinoic acid of exogenous and endogenous development of putative preneoplastic, glutathione S-transferase placental form-positive lesions in the livers of rats. 939 13

Retinoids, metabolites and synthetic derivatives of vitamin A (retinol), have been shown to inhibit carcinogenesis in various epithelial tissues in animal model systems and to have clinical efficacy as chemotherapeutic agents against certain types of cancer, including squamous cell carcinomas (SCCs). We examined the metabolism of [3H]retinol in normal human cell strains and SCC lines from the oral cavity and skin, and we report here that the cultured normal human epithelial cell strains esterified [3H]retinol to a much greater extent than the SCC lines. Furthermore, microsomal extracts of normal cell strains (e.g., OKF4) exhibited about 7-fold more palmityl-CoA-dependent, phenylmethylsulfonyl fluoride-resistant retinol esterification activity than extracts from SCC lines (e.g., SCC25). The fact that the esteriflcation of retinol was phenylmethylsulfonyl fluoride resistant suggests that the enzyme acyl-CoA:retinol acyltransferase is involved. Culture of both the normal and SCC lines in the presence of 1 microM all-trans-retinoic acid (RA) for 48 h enhanced the formation of [3H]retinyl esters from [3H]retinol. All of the cell lines examined can also metabolize [3H]retinol to [3H]RA, [3H]14-hydroxy-4,14-retroretinol, [3H]retinaldehyde, and [3H]3,4-didehydroretinol, but this metabolism occurs to varying extents in different cell lines. Culture of the cells in the presence of RA for 48 h did not affect the subsequent metabolism of [3H]retinol to [3H]RA and [3H]14-hydroxy-4,14-retroretinol, but it did reduce the metabolism of [3H]retinol to [3H]3,4-didehydroretinol. When cultured for 6-10 h in the presence of nanomolar concentrations of exogenous [3H]retinol, both the normal and SCC lines had much higher intracellular [3H]retinol concentrations, in the micromolar range. No correlation was seen between CRABP II or CRBP I mRNA levels and the levels of either intracellular [3H]retinol or [3H]retinol metabolism in these lines. The reduced ability to esterify retinol in these tumor cells may result in inappropriate cell growth and the loss of normal differentiation responses because of the lack of a sufficient amount of internal retinol stored as retinyl esters.
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PMID:Metabolism of all-trans-retinol in normal human cell strains and squamous cell carcinoma (SCC) lines from the oral cavity and skin: reduced esterification of retinol in SCC lines. 942 73

Since the late 1970s, a comprehensive search for cancer chemopreventive agents has been established in our Institute. A series of new retinoids have been synthesized and screened on the basis of established methodologies of experimental chemoprevention in vitro as well as in vivo. Pharmacological studies demonstrated that N-4-(carboxyphenyl)retinamide (RII) induces cell differentiation of HL-60 cells and inhibits dimethylnitrosamine-induced carcinogenesis of the forestomach in mice, 7,12-dimethylbenz[a]anthracene (DMBA)-induced papilloma in mouse skin, and DMBA-induced carcinogenesis of the buccal pouch in Syrian golden hamsters. It significantly promoted lymphoblastic transformation and activated macrophages. In further studies, RII significantly inhibited ornithine decarboxylase activity. After 6 months of chronic toxicological studies in rats and dogs, RII was recommended for clinical trial. Phase II studies found that RII is effective in treating oral and vulvar leukoplakia. It is also effective in treating myelodysplastic syndrome and dysplasia of uterine cervix. The chalcone retinoidal compounds were discovered when the search for new retinoids with less toxicity and higher potency led to third-generation retinoids, which were synthesized and screened. Structure-activity relationship studies found that 3,5-di-tert-butyl-4-methoxy-4-carboxyl chalcone (R9158) is the most active inhibitor of a variety of cancer cells. It has no effect on the Colony Forming Unit-Granulocyte/Macrophage (CFU-GM) of bone marrow in mice. In in vivo studies, R9158 showed a remarkable inhibition of chondrosarcoma in rats. It had no cross-resistance to vincristine, but was cross-resistant to all-trans retinoic acid. Red ginseng, a processed Panax ginseng, is considered a typical tonic in traditional Chinese medicine. Our studies demonstrated that red ginseng extract inhibited DMBA-induced skin papilloma significantly. Experiments showed that glycyrrhetinic acid inhibited croton oil-induced ear edema in mice. It also inhibited epidermal ornithine decarboxylase as well as the rapid DNA damage induced by the carcinogen benzo[a]pyrene (B[a]P). Our pharmacological studies demonstrated that Chinese gallotannin inhibited the malignant transformation of B[a]P-induced V79 cells in vitro and B[a]P-induced pulmonary adenoma in A/J mice in vivo significantly.
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PMID:Research and development of cancer chemopreventive agents in China. 959 Nov 87

To evaluate the practical value of natural beta-carotene (NbetaC) and to elucidate the apparent discrepancy between epidemiological observations and intervention trials on the role of beta-carotene (betaC) in tumor prevention, the genotoxicity and the antigenotoxicity of NbetaC and synthetic betaC crystal (SbetaCC) stereoisomers were studied comparatively using chromosome aberration analysis and the micronucleus test in human lymphocytes in vitro. NbetaC was extracted from the halotolerant algae Dunaliella salina. The NbetaC crystal (NbetaCC) preparation is about 70% all-trans (TbetaC) and 8% 9-cis (CbetaC). The NbetaC oil (NbetaCO) preparation is about 40% all-trans and 38% 9-cis. SbetaCC is more than 97% all-trans, and the 9-cis can not be detected. The mixture of betaC (betaCM) preparation is 74% SbetaCC and 26% NbetaC. Our results show no genotoxicity of 1-30 microg/ml NbetaCC, but this concentration of NbetaCC inhibited significantly gamma-ray-induced micronucleus formation in human lymphocytes in vitro. One to thirty microg/ml NbetaCO was most effective against both gamma-ray-induced and spontaneous micronucleus formation. However, no influence of NbetaCO on spontaneous chromosome aberrations in human lymphocytes in vitro was observed. NbetaCO suppressed significantly mitomycin C (MMC)-induced chromosome aberrations. One to thirty microg/ml SbetaCC induced a dose-dependent increase in micronucleus frequency, and also inhibited gamma-ray-induced micronucleus formation. No effect of betaCM on spontaneous chromosome aberrations was found. One to thirty microg/ml betaCM is more effective against MMC-induced chromosome aberrations than NbetaCO. These results suggest that CbetaC might play a critical role in the genotoxicity and antigenotoxicity of SbetaCC and NbetaC. The genotoxic activity of SbetaCC might be involved in carcinogenesis. NbetaC or betaCM could be of practical value in tumor prevention and supplementary treatment.
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PMID:Comparative studies on genotoxicity and antigenotoxicity of natural and synthetic beta-carotene stereoisomers. 975 99

During carcinogenesis, pancreatic acinar cells can dedifferentiate into ductal adenocarcinoma of the pancreas. DSL-6A/C1 cells represent an in vitro model of this carcinogenic sequence. This study was designed to examine the effects of retinoids on cell growth in DSL-6A/C1 cells and to characterize further the molecular mechanisms underlying the antiproliferative actions of retinoids. Treatment of DSL-6A/C1 cells with retinoids results in a time- and dose-dependent inhibition of cell growth, paralleled by a retinoid-mediated transactivation of a pTK::betaRAREx2-luciferase reporter construct transiently transfected into DSL-6A/C1 cells. Retinoid receptor expression was evaluated by reverse transcriptase polymerase chain reaction (RT-PCR) using subtype-specific primers and demonstrated expression of retinoic acid receptor alpha (RAR-alpha), RAR-beta and retinoid X receptor alpha (RXR-alpha). Using a panel of receptor subtype-specific agonists, the RAR-alpha specific agonist Ro 40-6055 was the most potent retinoid in terms of growth inhibition. Furthermore, all-trans-retinoic acid-mediated growth inhibition and transactivation was completely blocked by the RAR-alpha-specific antagonist Ro 41-5253. In summary, the RAR-alpha subtype predominantly mediates the antiproliferative effects of retinoids in DSL-6A/C1 cells. Furthermore, this cell system provides a feasible tool to study the molecular mechanisms underlying the growth inhibitory effects of retinoids in ductal pancreatic carcinoma cells derived from a primary acinar cell phenotype.
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PMID:Retinoic acid receptor alpha mediates growth inhibition by retinoids in rat pancreatic carcinoma DSL-6A/C1 cells. 982 68

Two recent papers demonstrate that prolactin plays an important role in the induction and progression of mammary tumours. Retinoids have been shown to be potent inhibitors of breast carcinogenesis. We studied expression of prolactin receptor mRNA in human breast cancer cell lines MCF-7, SKBR-3, T47D and BT-20 treated with and without retinoids using Northern blot and a quantitative polymerase chain reaction (PCR) method. In all cell lines, all-trans- and 9-cis-retinoic acid, as well as the retinoic acid receptor gamma (RAR-gamma) selective agonists CD2325 and CD437 (1 microM), were able to down-regulate prolactin receptor. After 1 h, a significant reduction was detectable and maximal effect was achieved after 24 h of treatment. Pretreatment with retinoic acid also reduced the prolactin-/prolactin receptor-dependent signal transduction and activation of transcription 5 (STAT-5) activation in T47D cells. Cycloheximide failed to abrogate the retinoic acid-induced decline in prolactin receptor mRNA levels, indicating that this effect was not dependent upon continuing protein synthesis. Similarly, no change in the stability of prolactin receptor mRNA was observed during 12 h of retinoic acid treatment. In conclusion, our results demonstrate that retinoids are able to inhibit the expression of prolactin receptor message, which encodes an important growth factor receptor in breast cancer cells. This action could be responsible for the anti-tumour effects of retinoids.
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PMID:Retinoic acid modulates prolactin receptor expression and prolactin-induced STAT-5 activation in breast cancer cells in vitro. 988 58

The effect of prolonged administration of all-trans-retinoic acid (RA) on sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine, and the labelling and apoptotic indices and immunoreactivity of transforming growth factor (TGF) alpha in the gastric cancers was investigated in Wistar rats. After 25 weeks of carcinogen treatment, the rats were given chow pellets containing 10% sodium chloride and subcutaneous injections of RA at doses of 0.75 or 1.5 mg kg(-1) body weight every other day. In week 52, oral supplementation with sodium chloride significantly increased the incidence of gastric cancers compared with the untreated controls. Long-term administration of RA at both doses significantly reduced the incidence of gastric cancers, which was enhanced by oral administration of sodium chloride. RA at both doses significantly decreased the labelling index and TGF-alpha immunoreactivity of gastric cancers, which were enhanced by administration of sodium chloride, and significantly increased the apoptotic index of cancers, which was lowered by administration of sodium chloride. These findings suggest that RA attenuates gastric carcinogenesis, enhanced by sodium chloride, by increasing apoptosis, decreasing DNA synthesis, and reducing TGF-alpha expression in gastric cancers.
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PMID:Attenuation by all-trans-retinoic acid of sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats. 1007 Aug 61

Multiple data suggest a relationship between thyroid hormone (triiodothyronine (T3)) and carcinogenesis. Studies on breast cancer have been inconclusive, suggesting contradictory effects of thyroid status and diseases. Recently, we reported that expression of the extracellular matrix glycoprotein tenascin-C is modulated by T3 during rat brain development. Because tenascin-C has been reported to have growth-, motility-, and angiogenic-promoting activities and to become upregulated during tumorigenesis in breast carcinoma and stromal cells, we analyzed the effects of T3 on tenascin-C expression in mammary epithelial cells. In this study, we showed that tenascin-C RNA expression was inhibited by T3 in normal un-transformed EpH4 mouse mammary epithelial cells expressing appropriate receptors. T3's action appeared to be due to a decreased half-life of the tenascin-C mRNA, with a maximum effect (85% at 100 nM) 48 h after addition. T3 also downregulated tenascin-C in the human mammary tumor cell line SKBR-3, which expresses endogenous thyroid receptors. Immunoprecipitation experiments confirmed that tenascin-C protein content was also decreased by T3 in EpH4 cells (70% reduction at 100 nM). Dexamethasone had a similar inhibitory effect (70% at 100 nM), whereas estradiol, the antiestrogen ICI 164,384, progesterone, and all-trans retinoic acid did not alter tenascin-C expression. Our data demonstrate an inhibitory action of T3 on tenascin-C expression in mammary epithelial cells that may play a role in the physiological regulation of this gene and in neoplastic processes.
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PMID:Inhibition of tenascin-C expression in mammary epithelial cells by thyroid hormone. 1007 37

Carotenoids are a family of pigments with at least 600 members. They derive from lycopene after steps of cyclisation, dehydrogenation and oxidation. It is their chemical structure that determines their physiochemical properties and, in part, their biological activities. About 50 carotenoids can be found in human diet and about 20 of them have been found in plasma and tissues. There is no RDA (Recommended Daily Allowance) for carotenoids. Quantities of carotenoids in diet are difficult to estimate, partly because methods used for the establishment of food composition tables were not specific and sensitive enough. Also, given values do not always take into account variations due to season and region of culture. Absorption of beta-carotene in humans has been the subject of numerous studies but only very little is known about other carotenoids. In general, absorption depends on bioavailability from the food matrix and solubility in micelles. After absorption through passive diffusion, carotenoids follow the chylomicrons metabolism. They are taken up by the liver and released in the blood stream in lipoproteins (VLDL). Carotenoids with no-substituted beta-ionone cycles (alpha and beta-carotene and beta-cryptoxanthin) have provitamin A activity. Highest activity has been found for all-trans beta-carotene. Not all steps of vitamin A biosynthesis and metabolism of other carotenoids have been clarified yet. Besides their provitamin A activity, carotenoids have numerous biological functions. They are efficient scavengers of free radicals, particularly of 1O2. In vitro they have been shown to protect LDL. However, results in vivo are inconsistent. Other functions include enhancement of gap junctions, immunomodulation and regulation of enzyme activity involved in carcinogenesis.
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PMID:[Carotenoids: 1. Metabolism and physiology]. 1021 Jul 43

Overexpression of cyclin D1 protein is observed in the majority of breast cancers, suggesting that dysregulated expression of cyclin D1 might be a critical event in breast cancer carcinogenesis. We investigated whether retroviral-mediated expression of cyclin D1 might affect all-trans-retinoic acid (ATRA)-mediated growth inhibition and differentiation of normal cultured human mammary epithelial cells (HMECs). HMECs treated with 1.0 microM ATRA undergo irreversible growth inhibition starting at 24 h and complete G0/G1-phase arrest by Day 3. Cyclin D1 protein levels are observed to decrease in association with the initiation of growth arrest starting at 24 h and then increase by approximately 35% on Day 3. Concomitant with this observed increase in cyclin D1, HMECs undergo morphologic changes consistent with progression to a more differentiated phenotype, including an increase in cell size, increased cell spreading, increased tonofilaments, and accumulation of cytoplasmic vesicles containing lipid. Dysregulated expression of cyclin D1 in HMECs results in inhibition of G0/G1-phase arrest mediated by ATRA. In addition, HMECs expressing exogenous cyclin D1 are resistant to differentiation by ATRA. Our results suggest that coordinated expression of cyclin D1 may be critical for normal mammary epithelial cell homeostasis, and dysregulated expression of cyclin D1 might result in retinoid resistance and promote mammary carcinogenesis.
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PMID:Dysregulated expression of cyclin D1 in normal human mammary epithelial cells inhibits all-trans-retinoic acid-mediated G0/G1-phase arrest and differentiation in vitro. 1032 55


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