Efficacy of Targretin on methylnitrosourea-induced mammary cancers: prevention and therapy dose-response curves and effects on proliferation and apoptosis.
ABSTRACT Various aspects of the chemopreventive and chemotherapeutic properties of the RXR receptor agonist Targretin (LGD 1069) were examined in the methylnitrosourea (MNU)-induced model of mammary cancer. The administration of Targretin at dose levels of 60, 20 or 6.7 mg/kg body wt/day by gavage decreased the number of mammary tumors by 96, 85 and 78%, respectively. When Targretin was administered in the diet at 92 and 275 mg/kg diet cancer multiplicities were reduced by 78 and 92%, respectively. A wider range of dietary doses of Targretin at 15, 50 and 150 mg/kg diet reduced the number of mammary tumors by 38, 55 and 70%, respectively. Treatment of rats with different regimens of Targretin (250 mg/kg diet) yielded cancer multiplicities of 4.3 for non-treated rats, 0.5 for rats treated continuously with Targretin, 2.1 for rats treated with Targretin for 8 weeks followed by 10 weeks of the control diet and 1.6 for rats treated with Targretin alternating 3 days on and 4 days off. Targretin was also examined as a therapeutic agent by treating rats with at least one palpable mammary tumor for 5 weeks. A high dose of Targretin (272 mg/kg diet) caused partial or complete regression of approximately 65% of the cancers over this time period. In contrast, in animals treated with 15 mg Targretin/kg diet only 1 of 12 cancers showed significant regression. Finally, the effect of a limited exposure to Targretin (7 days) on cell proliferation and apoptosis in small mammary tumors was determined. Targretin at 150 mg/kg diet strongly decreased proliferation (75%) and increased apoptosis (300%), while a lower dose of Targretin (15 mg/kg diet, which still prevented 30% of cancers) had no effect on apoptosis but did decrease cell proliferation. Determination of serum IGF1 levels showed that treatment of rats with highly effective doses of Targretin at 272 mg/kg diet or at 60 or 20 mg/kg body wt/day by gavage caused significantly decreased serum IGF1 levels.
Full-textDOI: · Available from: Vernon E Steele, Oct 06, 2014
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ABSTRACT: "In partial fulfillment of the requirements for the degree of Master of Science in Biomedical Sciences." Major advisor: Michael Pereira. Includes abstract. Document formatted into pages: v, 196 p. Title from title page of PDF document. Thesis (M.S.)--Medical University of Ohio, 2005. Bibliography: pages 64-66, 90-97, 125-131, 155-195. Text data with some col. graphics. Abstract and citation at ETD Center are HTML encoded; full-text in portable document format (PDF). System requirements: Internet connectivity; World Wide Web browser; PDF viewer. Mode of access: World Wide Web.
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ABSTRACT: Retinoids, vitamin A analogues that bind to retinoic acid receptor (RAR) or retinoid X receptor (RXR), play important roles in regulating cell proliferation, apoptosis, and differentiation. Recently, RXR-selective ligands, also referred to as rexinoids, have been investigated as potential chemopreventive agents for breast cancer. Our previous studies demonstrated that the rexinoid bexarotene significantly prevented ER-negative mammary tumourigenesis with less toxicity than naturally occurring retinoids in animal models. To determine whether bexarotene prevents cancer at the early stages during the multistage process of mammary carcinogenesis, we treated MMTV-erbB2 mice with bexarotene for 2 or 4 months. The development of preinvasive mammary lesions such as hyperplasias and carcinoma-in-situ was significantly inhibited. This inhibition was associated with reduced proliferation, but no induction of apoptosis. We also examined the regulation of a number of rexinoid-modulated genes including critical growth and cell cycle regulating genes using breast cell lines and mammary gland samples from mice treated with rexinoids. We showed that two of these genes (DHRS3 and DEC2) were modulated by bexarotene both in vitro and in vivo. Identification of these rexinoid-modulated genes will help us understand the mechanism by which rexinoid prevents cancer. Such rexinoid-regulated genes also represent potential biomarkers to assess the response of rexinoid treatment in clinical trials.British Journal of Cancer 05/2008; 98(8):1380-8. DOI:10.1038/sj.bjc.6604320 · 4.82 Impact Factor
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ABSTRACT: A rexinoid, targretin, and two retinoids, 9-cis retinoic acid (9cRA) and 4-hydroxyphenylretinamide (4HPR), were examined for their effects on gene expression in rat mammary gland, liver, and lung tissues. The chemopreventive effects of these agents have largely been attributed to their ability to interact with retinoic acid receptors (RAR) and/or retinoid X receptors (RXR). Targretin interacts with the RXR receptors. 9cRA interacts with both the RAR and RXR receptors, whereas 4HPR has a moderate affinity primarily for RAR gamma. Based on previous studies on mammary chemoprevention, targretin (150 mg/kg diet), 9cRA (100 mg/kg diet), and 4HPR (782 mg/kg diet), were administered to rats continually in their diet for 7 days. Tissue- and agent-specific expression differences were determined by comparing tissues from treated rats with those from rats given a control diet. There were significantly more changes associated with targretin than 9cRA or 4HPR. Only a limited number of expression changes were found with 4HPR treatment. For each organ, targretin- and 9cRA-treated tissues clustered closely together, whereas 4HPR-treated tissues clustered with the tissues from the control diet group. In contrast to 9cRA treatment, targretin treatment altered genes that involved fatty acid metabolism and modulation of various cytochromes P450 in the liver, clearly demonstrating the very disparate nature of these two retinoids. These expression signatures could provide useful pharmacodynamic biomarkers for retinoid treatment and chemoprevention.Molecular Cancer Therapeutics 05/2006; 5(4):1060-72. DOI:10.1158/1535-7163.MCT-05-0322 · 6.11 Impact Factor