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

The inhibitory effect of an aromatic retinoic acid analog, ethyl all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate, on bladder carcinogenesis in rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was evaluated. Administration of 50 ppm of aromatic retinoid in the diet before BBN in the drinking water reduced the incidence of papillary or nodular hyperplasia as a preneoplastic lesion of the bladder epithelium (P < 0.05). When given before, during or after BBN, it also greatly reduced the incidence of papilloma (P < 0.001 before BBN, P < 0.01 during or after BBN treatment), and slightly inhibited the development of cancer. Administration of 100 ppm of aromatic retinoid before or during BBN administration also reduced the incidences of papillary or nodular hyperplasia (P < 0.01 before BBN, P < 0.05 during BBN treatment), and its administration before, during or after BBN treatment greatly reduced the incidences of papilloma (P < 0.001), and cancer (P < 0.01 before or after BBN, P < 0.001 during BBN treatment). Similar results were obtained by assessing the effect of the retinoid on the average numbers of various epithelial lesions per 10 cm length of basement membrane of the bladder in tissue slices. These results show that the aromatic retinoid inhibits both the initiation and promotion of bladder carcinogenesis induced in rats by BBN, and that its effect is dose-dependent.
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PMID:Inhibitory effect of an aromatic retinoic acid analog on urinary bladder carcinogenesis in rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine. 741 79

The reversible inhibitory action of an aromatic analog of retinoic acid, ethyl all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate (aromatic retinoid) on bladder carcinogenesis was studied by biochemical and histopathological methods. fischer 344 female rats were fed a diet containing the aromatic retinoid (0, 12.5 or 50 ppm) for 56 days. On day 57, 60 or 70, 50 mg/kg body weight of N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN) in a volume of 0.3 ml was directly instilled intravesically through a urethral catheter. DNA damage in rat bladder epithelial cells 2, 24 and 48 hr after administration of BCPN was examined by measuring the change in sedimentation profile of the DNA in 5 approximately 20% alkaline sucrose gradients. DNA sedimentation was measured by a fluorometric procedure. Histopathological examination of the bladder epithelium was performed at the same time. Two hours after a 5-min exposure to BCPN, DNA damage at the urothelium was observed in rats fed the diet without the aromatic retinoid, but the damage was repaired after 24 and 48 hr. The highest dose of the aromatic retinoid almost completey prevented DNA damage by BCPN on days 57 and 60. A lower dose of the aromatic retinoid did not prevent DNA damage by BCPN on days 57, 60, and 70, while the higher dose did not prevent damage by BCPN on day 70. No histological changes were observed in the urothelium of rats treated with the aromatic retinoid and BCPN, and electron microscopy showed that the epithelium also remained normal. DNA damage was induced by BCPN at the urothelium, and the damage was inhibited by previous administration of the aromatic retinoid.
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PMID:Inhibition by an aromatic retinoid of DNA damage induced by the bladder carcinogen N-butyl-N-(3-carboxypropyl)nitrosamine. 741 80

Retinoids are important regulators of cervical epithelial cell differentiation and have been used in the treatment of cervical cancer. In the present study we evaluate the effects of retinoic acid on expression of biochemical markers of differentiation and expression of human papillomavirus reading frames encoding the early gene products E6 and E7 in normal and HPV16-immortalized cervical epithelial cell lines. Our results indicate that the differentiation markers cytokeratins K5 and K16 and transglutaminase type 1 are suppressed by all-trans-retinoic acid (RA). A marked concentration-dependent reduction in the level of of each mRNA is observed with maximal suppression at 1 microM. Each of the HPV16-immortalized cell lines (ECE16-1, ECE16-D1 and ECE16-D2) are more sensitive to the effects of RA than normal cells. The level of HPV16 transcript encoding E6/E7 is not significantly suppressed by 1 microM RA in ECE16-1 cells, but is suppressed in ECE16-D1 and ECE16-D2 cells. In addition, an increase in HPV transcripts encoding E6/E7 is observed at intermediate (10 and 100 nM) retinoic acid concentrations in ECE16-1 and ECE16-D2 cells, but not in ECE16-D1 cells. Our results show that retinoids regulate E6/E7 transcript levels in some cervical cell lines but not in others, suggesting that different cervical tumors may respond to retinoids via different mechanisms.
Carcinogenesis 1995 Feb
PMID:Retinoid regulation of cell differentiation in a series of human papillomavirus type 16-immortalized human cervical epithelial cell lines. 753 15

Retinoids have demonstrated activity in the prevention of second primary tumors in patients with non-small cell lung cancer (NSCLC). They also contribute to the normal growth and differentiation of human bronchial epithelial (HBE) cells. Because retinoids mediate their actions through retinoid nuclear receptors (RARs and RXRs), aberrant signaling through retinoid receptors could contribute to lung carcinogenesis. Using a lung carcinogenesis model consisting of normal, premalignant, and malignant HBE cells, we examined all-trans retinoic acid (t-RA)-induced changes in cellular growth. These studies revealed that t-RA treatment inhibited the growth of normal HBE cells, but premalignant and malignant HBE cells were relatively resistant to t-RA. Coincident with the development of retinoid refractoriness, basal expression of the retinoic acid nuclear receptor beta (RAR-beta) increased. Analysis of receptor function by gel shift and transient transfection assays of normal, premalignant, and malignant HBE cells demonstrated that receptor-DNA binding and transcriptional activation properties were intact in the t-RA-refractory malignant HBE cells. To compare these findings to NSCLCs in patients, we investigated retinoid receptor expression in NSCLC biopsies. A subset of the tumors expressed RAR-beta, reflecting the RAR-beta expression observed in the malignant HBE cells in culture. These findings demonstrate that retinoid receptor function was intact in the t-RA-refractory malignant HBE cell line, suggesting that the defect in retinoid signaling in this lung carcinogenesis model is not intrinsic to the retinoid receptors.
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PMID:Retinoid refractoriness occurs during lung carcinogenesis despite functional retinoid receptors. 758 41

Retinoid response pathways involve retinoic acid receptors (RARs) and retinoid X receptors. N-(4-hydroxyphenyl) retinamide (4-HPR), a derivative of all-trans-retinoic acid (RA) is currently in clinical trials as a chemopreventive agent for breast cancer. The issue whether 4-HPR mediates its biological actions via classical retinoid receptor pathways remains to be investigated. In this study, we provide several lines of evidence that 4-HPR mediates its biological actions via a novel pathway(s) that does not involve the classical retinoid receptor pathways. For example, 4-HPR was more potent than RA as an antiproliferative agent and inhibited growth of otherwise RA-resistant human breast carcinoma cells. Exposure to 4-HPR resulted in the generation of DNA fragmentation with subsequent cell death in both RA-positive estrogen receptor (ER)-positive as well as RA-refractory ER-negative breast carcinoma cell lines. N-(4-Methoxyphenyl)retinamide (4-MPR), which is the major 4-HPR metabolite in circulation, was biologically inert in this system. 4-HPR and 4-MPR bound poorly to the RAR alpha, beta and gamma in vitro and only minimally activated the retinoic acid receptor element (RARE) and retinoid X receptor response elements (RXREs) in human breast carcinoma cells. Neither 4-HPR nor 4-MPR are metabolized to any of the known conventional retinoids. In addition, 4-HPR or 4-MPR transactivation of RAREs or RXREs transfected into MCF-7 and MDA-MB-231 cells was not noted at 48 h. Nevertheless 4-HPR-mediated cell death was observed at 48 h, further suggesting that neither 4-HPR nor 4-MPR are metabolized to retinoids which activate the RAREs or RXREs in breast carcinoma cells. Furthermore, unlike RA, which exhibited anti-AP1 activity, 4-HPR inhibition of growth did not involve anti-AP1 activity. These results suggest that 4-HPR acts by a unique pathway that is not mediated by retinoid receptors.
Carcinogenesis 1995 Oct
PMID:N-(4-hydroxyphenyl)retinamide (4-HPR)-mediated biological actions involve retinoid receptor-independent pathways in human breast carcinoma. 758 55

Several phase II clinical studies of all-trans-retinoic acid (ATRA) have been conducted in acute promyelocytic leukemia (APL), an uncommon subtype of acute myeloid leukemia (AML). ATRA has been shown to induce complete remission (CR) in 64% to 96% of patients with APL, and with rapid resolution of the coagulopathy, which is a major cause of early morbidity and mortality. Although CRs induced with ATRA alone are usually not sustained and intensive antileukemic consolidation therapy is required to prolong remission, these findings indicate that a new approach of differentiation therapy is effective in treating patients with APL and may potentially be effective in other malignancies. The presence of the PML/retinoic acid receptor-alpha (PML/RAR-alpha) fusion gene, produced as a result of the unique chromosomal translocation in APL, is a marker of sensitivity to ATRA. Aside from the complications of hyperleukocytosis and the retinoic acid syndrome, ATRA therapy is generally well tolerated. An international study (Intergroup 0129), headed by the Eastern Cooperative Oncology Group, is currently under way to determine further the role of ATRA in the treatment of patients with APL. Given its success in APL, studies of ATRA in other hematologic malignancies are also being conducted. A better understanding of how retinoids modulate carcinogenesis will help determine if the results in APL can be realized in other malignancies treated with ATRA or other retinoids.
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PMID:All-trans-retinoic acid in acute promyelocytic leukemia and its potential in other hematologic malignancies. 783 84

Using 7,12-dimethylbenz[a]anthracene as the initiator and 12-O-tetradecanoyl-13-acetate as the tumor promoter on the dorsal skin of Sencar mice, we previously showed that pharmacological dietary all-trans-retinoic acid and beta-carotene inhibit the conversion of papillomas to carcinomas in a two-stage system of chemical carcinogenesis. The purpose of this study was to determine the influence of dietary retinoic acid and beta-carotene on retinoid and beta-carotene concentrations in skin and other tissues. We were unable to measure tissue retinoic acid because of the relatively limited amount of tissue available for analysis and the fast rate of metabolism. Different dietary levels of retinoic acid or beta-carotene did not influence total retinol of skin, papilloma, and carcinoma tissues, which all showed a concentration of approximately 1 +/- 0.5 microgram/g wet wt. Equally refractory to dietary retinoic acid or beta-carotene was serum retinol concentration. In contrast, dietary retinoic acid protected loss of liver retinol and retinyl palmitate, and beta-carotene caused an increase in beta-carotene and retinyl palmitate in liver but did not affect serum and liver retinol. We further investigated metabolic and functional aspects of retinoic acid in cultured mouse epidermal keratinocytes (LC-8 cells) and found that these cells actively metabolized [10,11-14C]retinoic acid to polar compounds. Isomers of retinoic acid were a minor product in the presence of cells and the major product when incubated in serum-containing medium in the absence of cells. From the functional point of view, exposure of LC-8 cells to 3 x 10(-6) M all-trans-retinoic acid (RA) caused a 75-fold induction in tissue transglutaminase and an approximately 9-fold induction in 10(-6) M RA at three days of culture. We conclude that retinoic acid spares endogenous retinol and that beta-carotene greatly enhances liver retinyl palmitate levels. Moreover we show that although mouse epidermal cells metabolize retinoic acid at a very high rate, they respond functionally by induction of tissue transglutaminase activity. Because this enzyme has been suggested to be involved in programmed cell death, we are presently investigating the possibility that it may be involved in the inhibition of carcinogenesis in mice fed pharmacological doses of RA.
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PMID:Retinol and beta-carotene concentrations in skin, papillomas and carcinomas, liver, and serum of mice fed retinoic acid or beta-carotene to suppress skin tumor formation. 791 Mar 92

We show that 9-cis-retinoic acid (9cRA) is a potent inhibitor of mammary carcinogenesis induced by N-nitroso-N-methylurea in Sprague-Dawley rats. Rats were first treated with a single dose of N-nitroso-N-methylurea (50 mg/kg body weight) and then fed non-toxic levels of 9cRA (120 or 60 mg/kg of diet). 9cRA was highly effective in reducing tumor incidence, average number of tumors per rat, and average tumor burden, as well as extending tumor latency. The combination of 9cRA with low levels of tamoxifen (TAM; fed at either 1.0 or 0.5 mg/kg of diet) was particularly effective; addition of 9cRA to a TAM regimen doubled the number of animals that were tumor-free at autopsy and significantly diminished tumor number and tumor burden. For suppression of carcinogenesis in vivo, 9cRA was much more potent than all-trans-retinoic acid, both as a single agent or in combination with TAM, although both retinoids had equivalent inhibitory effects on DNA synthesis in cultured human breast cancer cell lines. Both 9cRA and all-trans-retinoic acid induce the expression of the adhesion molecule, E-cadherin, in the SK-BR-3 cell line. We suggest that clinical evaluation of the combination of 9cRA and TAM, either for chemoprevention or for adjuvant therapy, should be considered.
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PMID:Prevention of breast cancer in the rat with 9-cis-retinoic acid as a single agent and in combination with tamoxifen. 806 53

The epithelium of the oral cavity is mostly nonkeratinizing. However, it undergoes an abnormal squamous differentiation with keratinization during vitamin A deficiency or oral carcinogenesis. Vitamin A analogues (retinoids) were found to be effective in preventing oral premalignant lesions and second primary cancers in the upper aerodigestive tract. Further development of retinoids for prevention and therapy of squamous cell carcinoma (SCC) requires a better understanding of their mechanism action on the growth and differentiation of SCC cells. We used cultured head and neck SCC (HNSCC) cell lines as a model system. Treatment of HNSCC cells with beta-all-trans-retinoic acid resulted in inhibition of growth (proliferation and colony formation) and suppression of squamous differentiation to varying degrees in the different cell lines. Because some of the malignant HNSCC cells recapitulate the main characteristics of keratinocyte squamous differentiation and responsiveness to retinoids, they can serve as a model for investigating the mechanism underlying the effects of retinoids on cell growth and differentiation. It is thought that nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs) mediate the above effects of retinoids by acting as DNA-binding transcription-modulating factors. We found that HNSCC cell lines express several nuclear RAR and that their level could be modulated by retinoids in some cell lines. An inverse relationship was found between RAR-beta expression and squamous differentiation. An analysis of RAR mRNA expression in head and neck cancer specimens revealed a decrease in RAR-beta in premalignant and malignant tissues relative to normal mucosa. The expression of this receptor increased in vivo after treatment with 13-cis-retinoic acid. These results implicate the loss of RAR-beta expression in the development of head and neck cancer and suggest that RAR-beta could serve as an intermediate marker in prevention trials.
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PMID:Suppression of squamous cell carcinoma growth and differentiation by retinoids. 813 25

In mouse dorsal skin multistage carcinogenesis models, tumor promotion can be mediated by chemical agents, but also by wounding or abrasion of the epidermis, suggesting that endogenous growth factors mediate this process. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is one such factor that has been reported to be produced by keratinocytes in vitro, and has been suggested both to stimulate keratinocyte proliferation, and also to be a chemoattractant for neutrophils and macrophages. In this study we examined the expression and function of GM-CSF in mouse skin following the application of tumor-promoting agents. Both single and multiple applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in accumulation of GM-CSF mRNA in the epidermis. Various phorbol and non-phorbol ester tumor promoters were found to induce increases in epidermal GM-CSF mRNA levels commensurate with their relative tumor promoting capabilities. Fluocinolone acetonide (FA) and tosyl phenylalanine chloromethyl ketone (TPCK), inhibitors of tumor promotion, inhibited tumor promoter-mediated GM-CSF accumulation, whereas all-trans-retinoic acid (RA) enhanced the TPA-induced increase. The retinoic acid analogue RO-109359 which, unlike RA, does not have tumor promoting activity per se, inhibited the TPA-induced increase in epidermal GM-CSF mRNA levels. When an antibody specific to GM-CSF was administered prior to TPA, the promoter-induced dermal inflammation and increase in epidermal dark cell number were reduced, yet promoter-induced epidermal hyperplasia was not. These findings implied that elevation of GM-CSF levels plays an important role in chemically-mediated mouse skin tumor promotion and principally via effects on promoter-induced inflammation and increased epidermal dark cell number.
Carcinogenesis 1994 Apr
PMID:Granulocyte-macrophage colony-stimulating factor (GM-CSF) is expressed in mouse skin in response to tumor-promoting agents and modulates dermal inflammation and epidermal dark cell numbers. 814 76


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