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Prevention of methylnitrosourea-induced mammary cancers by 9-cis-retinoic acid and/or vitamin D3

Prevention of methylnitrosourea-induced mammary cancers by 9-cis-retinoic acid and/or vitamin D3. Cope, Mark B.; Steele, Vernon E.; Eto, Isao; Juliana, Margaret M.; Hill, Donald L.; Grubbs, Clinton J. (Departments of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA). Oncology Reports, 9(3), 533-537 (English) 2002 Oncology Reports. CODEN: OCRPEW.Some commonly used reagents like 684-93-5 and 5300-03-8 are used in this experiment. ISSN: 1021-335X. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Section cross-reference(s): 4, 18 Two cancer chemopreventive agents, vitamin D3 and 9-cis-retinoic acid (9-cis-RA), were evaluated alone and in combination in the methylnitrosourea (MNU)-induced mammary cancer model. In this study, female Sprague-Dawley rats received MNU (50 mg/kg BW) at 50 days of age. Vitamin D3 and 9-cis-RA were administered in the diet beginning 3 days later. The groups were: Group 1, vehicle only; Group 2, 9-cis-RA (60 mg/kg diet); Group 3, vitamin D3 (10 mg/kg diet); Group 4, vitamin D3 (3.3 mg/kg diet); Group 5, 9-cis-RA (60 mg/kg diet) plus vitamin D3 (10 mg/kg diet); and Group 6, 9-cis-RA (60 mg/kg diet) plus vitamin D3 (3.3 mg/kg diet). Animals were obsd. daily for signs of toxicity and were palpated 2x/wk for mammary tumors. The study was terminated 150 days after treatment with MNU. The av. no. of mammary cancers was 6.7 in the animals receiving only the carcinogen. 9-Cis-RA alone caused a 23% decrease in mammary cancer multiplicity, while vitamin D3 alone actually caused slight increases of 17 and 16% at 10 and 3.3 mg/kg diet dose levels, resp. When the agents were given in combination, however, the 9-cis-RA plus the high dose of vitamin D caused a significant decrease (44%) in mammary cancer no., while the 9-cis-RA plus the low dose resulted in a 37% decrease. Thus, low doses of these agents that were not effective in preventing mammary cancer when given alone appeared to be active when given in combinations. Possible interactions between the retinoic acid receptors and vitamin D receptor may be responsible for the obsd. inhibition of mammary carcinogenesis. .

Ligand-bound RXR can mediate retinoid signal transduction during embryogenesis

Ligand-bound RXR can mediate retinoid signal transduction during embryogenesis. Lu, Hui-Chen; Eichele, Gregor; Thaller, Christina (V. and M. McLean Department of Biochemistry, Baylor College of Medicine, Houston, TX 77030, USA). Development (Cambridge, United Kingdom), 124(1), 195-203 (English) 1997 Company of Biologists. CODEN: DEVPED. ISSN: 0950-1991. DOCUMENT TYPE: Journal CA Section: 12 (Nonmammalian Biochemistry) Section cross-reference(s): 2 Retinoids regulate various aspects of vertebrate development through the action of two types of receptors, the retinoic acid receptors (RARs) and the retinoid-X-receptors (RXRs). Although RXRs bind 9-cis-retinoic acid (9cRA) with high affinity, in vitro expts. suggest that RXRs are for the most part not liganded, but serve as auxiliary factors forming heterodimers with liganded partner receptors such as RAR. Here we have used RXR-and RAR-specific ligands 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzo ic acid (LG69) and (E)-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-prope nyl]benzoic acid (TTNPB), and show that, in the context of an embryo, liganded RXR can mediate retinoid signal transduction. This conclusion emerges from examg. the induction of several retinoid-responsive genes in the limb bud (Hoxb-6/-8, RARb) and in the developing central nervous system (Hoxb-1, otx-2). RARb and Hoxb-1 genes were most effectively activated by a combination of TTNPB and LG69, suggesting that the activation of these genes benefits from the presence of ligand-bound RAR and ligand-bound RXR. Hoxb-6/-8 genes were most efficiently induced by LG69, suggesting that liganded RXR can activate these genes. The regulation of the expression of the otx-2 gene was complex; expression was repressed by TTNPB, but such repression was relieved when LG69 was provided together with TTNPB, suggesting that ligand-bound RXR can overcome repression of transcription exerted by liganded RAR.In this experiment, several chemicals are used like 5300-03-8 Based on these findings, we propose that in our exptl. system in which ligands are provided exogenously, transcriptional regulation of several genes involves liganded RXR. .