Topic
Fluasterone
About: Fluasterone is a research topic. Over the lifetime, 24 publications have been published within this topic receiving 994 citations. The topic is also known as: Fluasterone & HE 2500.
Papers
TL;DR: All‐trans‐N‐(4‐hydroxy phenyl)retinamide (4‐HPR) (alone and in combination with tamoxifen), 2‐difluoromethylornithine (DFMO), nonsteroidal antiinflammatory drugs (aspirin, piroxicam, sulindac), oltipraz, and dehydroepiandrostenedione (DHEA).
Abstract: Clinical chemoprevention trials of more than 30 agents and agent combinations are now in progress or being planned. The most advanced agents are well known and are in large Phase III chemoprevention intervention trials or epidemiological studies. These drugs include several retinoids [e.g., retinol, retinyl palmitate, all-trans-retinoic acid, and 13-cis-retinoic acid], calcium, Beta carotene, vitamin E, tamoxifen, and finasteride. Other newer agents are currently being evaluated in or being considered for Phase II and early Phase III chemoprevention trials. Prominent in this group are all-trans-N-(4-hydroxy phenyl)retinamide (4-HPR) (alone and in combination with tamoxifen), 2-difluoromethylornithine (DFMO), nonsteroidal antiinflammatory drugs (aspirin, piroxicam, sulindac), oltipraz, and dehydroepiandrostenedione (DHEA). A third group is new agents showing chemopreventive activity in animal models, epidemiological studies, or in pilot clinical intervention studies. They are now in preclinical toxicology testing or Phase I safety and pharmacokinetics trials preparatory to chemoprevention efficacy trials. These agents include S-allyl-l-cysteine, curcumin, DHEA analog 8354 (fluasterone), genistein, ibuprofen, indole-3-carbinol, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, sulindac sulfone, tea extracts, ursodiol, vitamin D analogs, and p-xylyl selenocyanate. A new generation of agents and agent combinations will soon enter clinical chemoprevention studies based primarily on promising chemopreventive activity in animal models and in mechanistic studies. Among these agents are more efficacious analogs of known chemopreventive drugs including novel carotenoids (e.g., alpha-carotene and lutein). Also included are safer analogs which retain the chemopreventive efficacy of the parent drug such as vitamin D3 analogs. Other agents of high interest are aromatase inhibitors (e.g., (+)-vorozole), and protease inhibitors (e.g., Bowman-Birk soybean trypsin inhibitor). Combinations are also being considered, such as vitamin E with l-selenomethionine. Analysis of signal transduction pathways is beginning to yield classes of potentially active and selective chemopreventive drugs. Examples are ras isoprenylation and epidermal growth factor receptor inhibitors.
156 citations
TL;DR: A simple mathematical model has been developed to describe the combined effect of cosolvency and complexation on nonpolar drug solubilization that explains the decline in drug Solubility produced by low cosolvent concentrations as well as the increase in the solubilityproduced by high cosolent concentrations that are observed at all cyclodextrin concentrations.
78 citations
Journal Article•
TL;DR: Two synthetic steroids are developed, 16 alpha-fluoro-5-androstan-17-one and 16alpha-fluoros-5 alpha-androStan- 17-one, which lack specific side-effects of DHEA treatment and demonstrate greater potency, and may have therapeutic application as drugs for humans.
Abstract: Treatment of laboratory mice and rats with the adrenal steroid, dehydroepiandrosterone (DHEA), produces antiobesity and broad spectrum tumor chemopreventive activity. Certain side effects are associated with DHEA administration which could limit its usefulness as a drug. DHEA can be metabolized into both testosterone and estrone and also increases liver weight and liver catalase activity. We have developed two synthetic steroids, 16 alpha-fluoro-5-androstan-17-one and 16 alpha-fluoro-5 alpha-androstan-17-one, which, unlike DHEA, do not stimulate uterine weight in sexually immature female rats or seminal vesicle weight in castrated male rats, nor stimulate liver weight and liver catalase activity in mice. 16 alpha-Fluoro-5-androsten-17-one is also about three times as potent as DHEA as an antiobesity agent and is more active when administered p.o. in inhibiting [3H]-7,12-dimethylbenz(a)-anthracene binding to skin DNA and tetradecanoylphorbol-13-acetate stimulation of epidermal [3H]thymidine incorporation in the mouse, two effects believed to be important in the tumor preventive action of DHEA. 16 alpha-Fluoro-5 alpha-androstan-17-one is as active as 16 alpha-fluoro-5-androsten-17-one in inhibiting [3H]-7,12-dimethylbenz(a)anthracene binding to skin DNA and tetradecanoylphorbol-13-acetate stimulation in epidermal [3H]thymidine incorporation but, on the contrary, is not more active than DHEA as an antiobesity drug. Compounds such as 16 alpha-fluoro-5-androsten-17-one and 16 alpha-fluoro-5 alpha-androstan-17-one, which lack specific side-effects of DHEA treatment and demonstrate greater potency, may have therapeutic application as drugs for humans.
67 citations
TL;DR: Mice with specific (and human-like) genetic susceptibilities for cancer provide powerful new tools for testing and characterizing interventions that may inhibit the process of carcinogenesis in humans.
Abstract: Progress in mechanism-based cancer prevention research may be facilitated by the use of animal models displaying specific genetic susceptibilities for cancer such as mice deficient in the p53 tumor suppressor gene, the most frequently altered gene in human cancer. We observed in p53-knockout (p53-/-) mice that calorie restriction (CR; 60% of the control group's intake of carbohydrate energy) increased the latency of spontaneous tumor development (mostly lymphomas) ∼75%, decreased serum insulin-like growth factor (IGF)-1 and leptin levels, significantly slowed thymocyte cell cycle traverse and induced apoptosis in immature thymocytes. In heterozygous p53-deficient (p53+/-) mice, CR and 1 d/wk of food deprivation each significantly delayed spontaneous tumor development (a mix of lymphomas, sarcomas and epithelial tumors) and decreased serum IGF-1 and leptin levels even when begun late in life. We have also developed a rapid and relevant p53+/- mouse mammary tumor model by crossing p53-deficient mice with MMTV-Wnt-1 transgenic mice, and found that CR and 1 d/wk food deprivation significantly increased mammary tumor latency (greater than twofold) and reduced the mean serum IGF-1 and leptin levels to <50% of that of control mice (P < 0.0001). In addition, fluasterone, fenretinide and soy each delayed tumor development but had little effect on IGF-1 or leptin levels. We have capitalized on the susceptibility of p53+/- mice to chronic, low dose, aromatic amine-induced bladder carcinogenesis to develop a useful model for evaluating bladder cancer prevention approaches such as cyclooxygenase-2 inhibition. As demonstrated by these examples, mice with specific (and human-like) genetic susceptibilities for cancer provide powerful new tools for testing and characterizing interventions that may inhibit the process of carcinogenesis in humans.
66 citations
TL;DR: Fluasterone (DHEF) treatments improved functional recovery in a rat TBI model and suggest an exciting potential use for this agent in the clinical treatment of traumatic brain injury.
Abstract: The purpose of this study was to investigate the efficacy of a novel steroid, fluasterone (DHEF, a dehydroepiandrosterone (DHEA) analog), at improving functional recovery in a rat model of traumatic brain injury (TBI). The lateral cortical impact model was utilized in two studies of efficacy and therapeutic window. DHEF was given (25 mg/kg, intraperitoneally) at the initial time point and once a day for 2 more days. Study A included four groups: sham injury, vehicle treated (n = 22); injured, vehicle treated (n = 30); injured, pretreated (5–10 min prior to injury, n = 24); and injured, posttreated (initial dose 30 min postinjury, n = 15). Study B (therapeutic window) included five groups: sham injury, vehicle treated (n = 17); injured, vehicle treated (n = 26); and three posttreatment groups: initial dose at 30 min (n = 18), 2 h (n = 23), or 12 h (n = 16) postinjury. Three criteria were used to grade functional recovery. In study A, DHEF improved beam walk performance both with pretreatment (79%) and 30-min posttreatment group (54%; p < 0.01, Dunnett vs. injured vehicle). In study B, the 12-h posttreatment group showed a 97% improvement in beam walk perfomance (p < 0.01, Dunnett). The 30-min and 12-h posttreatment groups showed a decreased incidence of falls from the beam, which reached statistical significance (p < 0.05, Dunnett). Tests of memory (Morris water maze) and neurological reflexes both revealed significant improvements in all DHEF treatment groups. In cultured rat mesangial cells, DHEF (and DHEA) potently inhibited interleukin-1β–induced cyclooxygenase-2 (COX2) mRNA and prostaglandin (PGE2) production. In contrast, DHEF treatment did not alter injury-induced COX2 mRNA levels in the cortex or hippocampus. However, DHEF (and DHEA) relaxed ex vivo bovine middle cerebral artery preparations by about 30%, with an IC50 ≈ 40 μM. This was a direct effect on the vascular smooth muscle, independent of the endothelial cell layer. Fluasterone (DHEF) treatments improved functional recovery in a rat TBI model. Possible mechanisms of action for this novel DHEA analog are discussed. These findings suggest an exciting potential use for this agent in the clinical treatment of traumatic brain injury.
52 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2011 | 1 |
| 2010 | 1 |
| 2009 | 1 |
| 2006 | 3 |
| 2005 | 1 |
| 2004 | 2 |