Selective estrogen receptor modulators: discrimination of agonistic versus antagonistic activities by gene expression profiling in breast cancer cells

Selective estrogen receptor modulators (SERMs) such as tamoxifen are effective in the treatment of many estrogen receptor-positive breast cancers and have also proven to be effective in the prevention of breast cancer in women at high risk for the disease. The comparative abilities of tamoxifen versus raloxifene in breast cancer prevention are currently being compared in the Study of Tamoxifen and Raloxifene trial. To better understand the actions of these compounds in breast cancer, we have examined their effects on the expression of approximately 12,000 genes, using Affymetrix GeneChip microarrays, with quantitative PCR verification in many cases, categorizing their actions as agonist, antagonist, or partial agonist/antagonist. Analysis of gene stimulation and inhibition by the SERMs trans-hydroxytamoxifen (TOT) and raloxifene (Ral) or ICI 182,780 (ICI) and by estradiol (E2) in estrogen receptor-containing MCF-7 human breast cancer cells revealed that (a) TOT was the most E2-like of the three compounds, (b) all three compounds either partially or fully antagonized the action of E2 on most genes, with the order of antagonist activity being ICI > Ral > TOT, (c) TOT and Ral, but not ICI, displayed partial agonist/partial antagonist activity on a number of E2-regulated genes, (d) several stimulatory cell cycle-related genes were down-regulated exclusively by ICI, (e) the estrogen-like activity of Ral nearly always overlapped with that of TOT, indicating that Ral has little unique agonist activity different from that of TOT, and (f) some genes were specifically up-regulated by TOT but not Ral, ICI, or E2. Hence, gene expression profiling can discern fundamental differences among SERMs and provides insight into the distinct biologies of TOT, Ral, and ICI in breast cancer.     

Intimate partner violence: implications for nursing

Intimate partner violence is responsible for 30% of female homicides in the U. S. and has multiple negative health consequences. It is identified as one of the objectives in Healthy People 2010. Women are more likely to be assaulted by a current or former intimate partner than an acquaintance, family member, friend, or stranger. Universal screening is advocated as an effective approach in identifying affected women. There exists a few states mandating report of women with injuries resulting from IPV but it is only clearly mandated in California. Interventions to address the problem include those focused on increasing identification and screening, and treatment of intimate partner violence. This paper reviews the epidemiology, identification and screening, and interventions for IPV. The role for nursing is discussed concluding with directions for further investigation.     

Excipient effects on in vitro cytotoxicity of a novel paclitaxel self-emulsifying drug delivery system

Paclitaxel is a potent chemotherapeutic agent currently administered intravenously in polyoxyethylated castor oil (Cremophor EL) and dehydrated ethanol (1:1) for the treatment of solid tumors. The objective of this work was to develop a novel self-emulsifying drug delivery system (SEDDS) devoid of cremophor for the i.v./oral delivery of paclitaxel and to investigate the in vitro cytotoxicity of the combined excipients. The SEDDS formulations were characterized in terms of droplet size using a ternary phase diagram. The Caco-2 cell line was used to monitor the cytotoxicity of the excipients. Cell viability was determined colorimetrically at 570 nm utilizing the MTT assay. The distribution of the formulations on the phase diagram indicated the presence of macroemulsions ( approximately 1 microm), submicron emulsions (50-200 nm), and microemulsions (below 10 nm). An increase in the sodium deoxycholate excipient content led to an increase in physical stability but caused more chemical degradation of the drug and more cytotoxicity. The drug in the novel SEDDS was chemically stable for at least 1 year when kept as a two-part formulation. The drug loading was increased by approximately fivefold compared to the marketed i.v. formulation; the excipients presented a significantly reduced cytotoxicity and led to a stable microemulsion.     

Primary diffuse leptomeningeal glioneuronal tumors of the central nervous system: Report of three cases and review of literature

Abstract

Primary diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare tumors, recently recognized as a unique entity based on their unique pathologic and clinical characteristics. We report three cases of DLGNT and compare their clinical characteristics and presentation with other reported cases, and with primary leptomeningeal gliomatosis. Because their prognosis is better than that of diffuse leptomeningeal gliomatosis, and pathologic diagnosis may be difficult, clinicians should consider this diagnosis in patients who present with new neurological symptoms, hydrocephalus and diffuse leptomeningeal enhancement on MRI. Further studies are required to better understand the unique biological characteristics of these tumors and to improve therapy.     

Ability of Doxorubicin-Loaded Nanoparticles to Overcome Multidrug Resistance of Tumor Cells After Their Capture by Macrophages

Purpose. Investigation of the ability of doxorubicin-loaded nanoparticles (NP/Dox) to overcome multidrug resistance (MDR) when they have first been taken up by macrophages. Methods. The growth inhibition of P388 sensitive (P388) and resistant (P388/ADR) tumor cells was evaluated in a coculture system consisting of wells with two compartments. The tumor cells were seeded into the lower compartment, the macrophages were introduced into the upper part in which the drug preparations were also added. Results. Doxorubicin exerted lower cytotoxicity on tumor cells in coculture compared with direct contact. In P388/ADR, NP/Dox cytotoxicity was far higher than that of free doxorubicin (Dox). Three different formulations of cyclosporin A (either free (CyA), loaded to nanoparticles (NP/CyA) or in a combined formulation with doxorubicin (NP/Dox-CyA)), were added to modulate doxorubicin efficacy. The addition of cyclosporin A to Dox increased drug cytotoxicity. Both CyA added to NP/Dox and NP/Dox-CyA were able to bypass drug resistance. Conclusions. Despite the barrier role of macrophages, NP/Dox remained far more cytotoxic than Dox against P388/ADR. Both NP/ Dox + CyA and NP/Dox-CyA allowed to overcome MDR, but the last one should present greater advantagein vivo by confining both drugs in the same compartment, hence reducing the adverse effects.     

Influence of emulsion droplet surface charge on indomethacin ocular tissue distribution

The aim of this study was to compare the corneal penetration of indomethacin from Indocollyre [a marketed hydro-poly(ethylene glycol) (PEG) ocular solution] to that of a negatively and a positively charged submicron emulsion. Male albino rabbits were separated randomly into three groups and each group (N = 15) was treated with either one drop of radiolabeled 0.1% Indocollyre, or 0.1% indomethacin positively or negatively charged submicron emulsion, respectively. The rabbits were sacrificed at selected time points and the eyes were enucleated. The eyes were dissected into the different tissues: cornea, conjunctiva, aqueous humor, iris, lens, vitreous, sclera, and retina. The samples were weighed before radioactivity counting. Regardless of the preparation instilled, the highest concentration of indomethacin was achieved in the cornea followed by conjunctiva, sclera retina, and aqueous humor. However, the positively charged emulsion provided significantly higher drug levels than the control solution and negatively charged emulsion only in the aqueous humor and sclera-retina. Furthermore, the spreading coefficient of the positively charged emulsion on cornea is four times higher than that of the negatively charged emulsion. It was therefore deduced that the positively charged submicron emulsions have better wettability properties on the cornea compared to either saline or the negatively charged emulsion. The positive charge may prolong the residence time of the drop on the epithelial layer of the cornea and thus enable better drug penetration through the cornea to the internal tissues of the eye, as confirmed by the animal studies.     

5-HT(1A) and 5-HT(7) receptor crosstalk in the regulation of emotional memory: Implications for effects of selective serotonin reuptake inhibitors

This study utilized pharmacological manipulations to analyze the role of direct and indirect activation of 5-HT₇ receptors (5-HT₇Rs) in passive avoidance learning by assessing emotional memory in male C57BL/6J mice. Additionally, 5-HT₇R binding affinity and 5-HT₇R-mediated protein phosphorylation of downstream signaling targets were determined. Elevation of 5-HT by the selective serotonin reuptake inhibitor (SSRI) fluoxetine had no effect by itself, but facilitated emotional memory performance when combined with the 5-HT_1AR antagonist NAD-299. This facilitation was blocked by the selective 5-HT₇R antagonist SB269970, revealing excitatory effects of the SSRI via 5-HT₇Rs. The enhanced memory retention by NAD-299 was blocked by SB269970, indicating that reduced activation of 5-HT_1ARs results in enhanced 5-HT stimulation of 5-HT₇Rs. The putative 5-HT₇R agonists LP-44 when administered systemically and AS19 when administered both systemically and into the dorsal hippocampus failed to facilitate memory. This finding is consistent with the low efficacy of LP-44 and AS19 to stimulate protein phosphorylation of 5-HT₇R-activated signaling cascades. In contrast, increasing doses of the dual 5-HT_1AR/5-HT₇R agonist 8-OH-DPAT impaired memory, while co-administration with NAD-299 facilitated of emotional memory in a dose-dependent manner. This facilitation was blocked by SB269970 indicating 5-HT₇R activation by 8-OH-DPAT. Dorsohippocampal infusion of 8-OH-DPAT impaired passive avoidance retention through hippocampal 5-HT_1AR activation, while 5-HT₇Rs appear to facilitate memory processes in a broader cortico-limbic network and not the hippocampus alone.