Lubet, R. A. et al. Efficacy of Targretin on methylnitrosourea-induced mammary cancers: prevention and therapy dose-response curves and effects on proliferation and apoptosis. Carcinogenesis 26, 441-448

Division of Cancer Prevention, National Cancer Institute, Executive Plaza North, Suite 2110, 6130 Executive Boulevard, Bethesda, MD 20852, USA.
Carcinogenesis (Impact Factor: 5.33). 03/2005; 26(2):441-8. DOI: 10.1093/carcin/bgh338
Source: PubMed

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.

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    • "MNU-induced tumors are hormonally responsive and display many of the histopathological characteristics of human breast cancer [21]. Unlike clonogenic cancer models, individual in situ MNU-induced tumors have a highly variable growth rate [22]. Therefore, multi-modality imaging was performed using small animal MR and PET to correlate FDG and [18F]ISO-1 image-derived PET outcome measures as a means of predicting future changes in tumor volume. "
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    ABSTRACT: The sigma-2 receptor is expressed in higher density in proliferating (P) tumor cells versus quiescent (Q) tumor cells, thus providing an attractive target for imaging the proliferative status (i.e., P:Q ratio) of solid tumors. Here we evaluate the utility of the sigma-2 receptor ligand 2-(2-[(18)F]fluoroethoxy)-N-(4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butyl)-5-methyl-benzamide, [(18)F]ISO-1, in two different rodent models of breast cancer. In the first study, small animal Positron Emission Tomography (PET) imaging studies were conducted with [(18)F]ISO-1 and (18)FDG in xenografts of mouse mammary tumor 66 and tracer uptake was correlated with the in vivo P:Q ratio determined by flow cytometric measures of BrdU-labeled tumor cells. The second model utilized a chemically-induced (N-methyl-N-nitrosourea [MNU]) model of rat mammary carcinoma to correlate measures of [(18)F]ISO-1 and FDG uptake with MR-based volumetric measures of tumor growth. In addition, [(18)F]ISO-1 and FDG were used to assess the response of MNU-induced tumors to bexarotene and Vorozole therapy. In the mouse mammary 66 tumors, a strong linear correlation was observed between the [(18)F]ISO-1 tumor: background ratio and the proliferative status (P:Q ratio) of the tumor (R = 0.87). Similarly, measures of [(18)F]ISO-1 uptake in MNU-induced tumors significantly correlated (R = 0.68, P<0.003) with changes in tumor volume between consecutive MR imaging sessions. Our data suggest that PET studies of [(18)F]ISO-1 provide a measure of both the proliferative status and tumor growth rate, which would be valuable in designing an appropriate treatment strategy.
    PLoS ONE 09/2013; 8(9):e74188. DOI:10.1371/journal.pone.0074188 · 3.23 Impact Factor
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    • "This antiproliferative effect is much more profound than that of gefitinib, which only reduced the mammary epithelial proliferation by 20% (Lu et al, 2003). Other investigators have published results showing that bexarotene inhibits proliferation in methylnitrosourea-induced mammary cancers in rats by approximately 75% (Lubet et al, 2005; Christov et al, 2007). However, the 75% reduction was observed in methylnitrosourea-induced rat tumours, while the 35–40% reduction was observed in normal mammary glands in MMTV-erbB2 mice. "
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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 · 4.84 Impact Factor
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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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