Arsenic trioxide-mediated cytotoxicity and apoptosis in prostate and ovarian carcinoma cell lines. (57/1663)

We studied the effect of arsenic trioxide (As2O3) on prostate and ovarian carcinoma cell lines. As2O3 has been shown to be effective in leukemia, and acute promyelocytic leukemia in particular, both in vitro and in vivo. As model cell lines, we used DU145 and PC-3 for prostate cancer and MDAH 2774 for ovarian cancer. New modalities of treatment are essential in these kinds of cancers, which produce a high death toll. The 3-(4,5-dimethyl-thiazoyl-2-yl)-2,5-diphenyl-tetrazolium bromide assay was used to evaluate cytotoxicity. Flow cytometric analysis and mono-oligo nucleosome detection-based ELISA were used to determine the apoptosis. Isobologram analysis was used to evaluate synergism and/or the additive effects of As2O3 and conventional chemotherapeutic agents. We clearly demonstrated that As2O3 has significant cytotoxic effect on both prostate and ovarian carcinoma cell lines. The dose range of As2O3 in all three cell lines was approximately 10(-6) M. The mechanism underlying cytotoxicity of As2O3 was shown to be apoptosis. The experiments by butylated hydroxyanisole showed that the cytotoxic effect of As2O3 was not through superoxide generation. There was no synergism, but the additive effects of As2O3 were demonstrated with cisplatin, adriamycin, and etoposide. We strongly suggest that As2O3 alone or in combination with conventional chemotherapeutic agents be evaluated further as a new agent for the treatment of prostate and ovarian cancers.  (+info)

Magnetic resonance imaging of atherosclerotic plaque with ultrasmall superparamagnetic particles of iron oxide in hyperlipidemic rabbits. (58/1663)

BACKGROUND: Based on the observation that ultrasmall superparamagnetic particles of iron oxides (USPIOs) are phagocytosed by cells of the mononuclear phagocytic system, the purpose of this study was to evaluate their use as a marker of atherosclerosis-associated inflammatory changes in the vessel wall before luminal narrowing is present. METHODS AND RESULTS: Experiments were conducted on 6 heritable hyperlipidemic and 3 New Zealand White rabbits. 3D MR angiography (MRA) of the thoracic aorta was performed on all rabbits by use of a conventional paramagnetic contrast agent that failed to reveal any abnormalities. One week later, all rabbits except 1 of the hyperlipidemic animals were injected with a USPIO contrast agent (Sinerem, Guerbet) at a dose of 1 mmol Fe/kg. 3D MRA data sets collected over the subsequent 5 days showed increasing signal in the aortic lumen. Whereas the aortic wall of the control rabbits remained smooth and bright, marked susceptibility effects became evident on day 4 within the aortic walls of hyperlipidemic rabbits. Ex vivo imaging of aortic specimens confirmed the in vivo results. Histopathology documented marked Fe uptake in macrophages embedded in atherosclerotic plaque of the hyperlipidemic rabbits. Electron microscopy showed multiple cytoplasmic Fe particles in macrophages. No such changes were seen in control rabbits or in the hyperlipidemic rabbit that had not received Sinerem. CONCLUSIONS: USPIOs are phagocytosed by macrophages in atherosclerotic plaques of the aortic wall of hyperlipidemic rabbits in a quantity sufficient to cause susceptibility effects detectable by MRI.  (+info)

Monolayers of derivatized poly(L-lysine)-grafted poly(ethylene glycol) on metal oxides as a class of biomolecular interfaces. (59/1663)

We report on the design and characterization of a class of biomolecular interfaces based on derivatized poly(l-lysine)-grafted poly(ethylene glycol) copolymers adsorbed on negatively charged surfaces. As a model system, we synthesized biotin-derivatized poly(l-lysine)-grafted poly(ethylene glycol) copolymers, PLL-g-[(PEGm)((1-x)) (PEG-biotin)(x)], where x varies from 0 to 1. Monolayers were produced on titanium dioxide substrates and characterized by x-ray photoelectron spectroscopy. The specific biorecognition properties of these biotinylated surfaces were investigated with the use of radiolabeled streptavidin alone and within complex protein mixtures. The PLL-g-PEG-biotin monolayers specifically capture streptavidin, even from a complex protein mixture, while still preventing nonspecific adsorption of other proteins. This streptavidin layer can subsequently capture biotinylated proteins. Finally, with the use of microfluidic networks and protein arraying, we demonstrate the potential of this class of biomolecular interfaces for applications based on protein patterning.  (+info)

Monocrystalline iron oxide nanoparticles: possible solution to the problem of surgically induced intracranial contrast enhancement in intraoperative MR imaging. (60/1663)

BACKGROUND AND PURPOSE: Intraoperative MR imaging is increasingly being used to control the extent of surgical resection; however, surgical manipulation itself causes intracranial contrast enhancement, which is a source of error. Our purpose was to investigate the potential of monocrystalline iron oxide nanoparticles (MIONs) to solve this problem in an animal model. METHODS: In male Wistar rats, surgical lesions of the brain were produced. The animals underwent MR examination immediately afterward. In the first group, a paramagnetic contrast agent was administered, whereas the second group of animals received MIONs 1 day before surgery. In a third group of animals, malignant glioma cells were stereotactically implanted in the caudoputamen. Two weeks later, MIONs were IV injected and the tumor was (partially) resected. Immediately after resection, MR examination was performed to determine the extent of residual tumor. RESULTS: Surgically induced intracranial contrast enhancement was seen in all animals in which a paramagnetic contrast agent was used. Conversely, when MIONs had been injected, no signal changes that could be confused with residual tumor were detected. In the animals that had undergone (partial) resection of experimental gliomas, MR assessment of residual tumor was possible without any interfering surgically induced phenomena. CONCLUSION: Because MIONs are stored in malignant brain tumor cells longer than they circulate in the blood, their use offers a promising strategy to avoid surgically induced intracranial contrast enhancement, which is known to be a potential source of error in intraoperative MR imaging.  (+info)

Interactions of herpes simplex virus type 1 with ND10 and recruitment of PML to replication compartments. (61/1663)

Many of the events required for productive herpes simplex virus type 1 (HSV-1) infection occur within globular nuclear domains called replication compartments, whose formation appears to depend on interactions with cellular nuclear domains 10 (ND10). We have previously demonstrated that the formation of HSV-1 replication compartments involves progression through several stages, including the disruption of intact ND10 (stage I to stage II) and the formation of PML-associated prereplicative sites (stage III) and replication compartments (stage IV) (J. Burkham, D. M. Coen, and S. K. Weller, J. Virol. 72:10100-10107, 1998). In this paper, we show that some, but not all, PML isoforms are recruited to stage III foci and replication compartments. Genetic experiments showed that the recruitment of PML isoforms to stage III prereplicative sites and replication compartments requires the localization of the HSV-1 polymerase protein (UL30) to these foci but does not require polymerase catalytic activity. We also examined the stages of viral infection under conditions affecting ND10 integrity. Treatment with factors that increase the stability of ND10, arsenic trioxide and the proteasome inhibitor MG132, inhibited viral disruption of ND10, formation of replication compartments, and production of progeny virus. These results strengthen the previously described correlation between ND10 disruption and productive viral infection.  (+info)

Drug approval summaries: arsenic trioxide, tamoxifen citrate, anastrazole, paclitaxel, bexarotene. (62/1663)

This report summarizes information on drugs recently approved by the Food and Drug Administration, Office of Drug Evaluation I, Division of Oncology Drug Products. Five applications supporting new claims will be discussed: Trisenox (arsenic trioxide) for induction of remission and consolidation in patients with acute promyelocytic leukemia who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose disease is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression; Nolvadex (tamoxifen citrate) in women with ductal carcinoma in situ, following breast surgery and radiation, to reduce the risk of invasive breast cancer; Arimidex (anastrazole) for first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer; Taxol (paclitaxel), 175 mg/m(2) by 3 h infusion in combination with cisplatin for first-line treatment of advanced ovarian cancer; and Targretin gel (bexarotene) for the topical treatment of cutaneous lesions in patients with stage IA and IB cutaneous T-cell lymphoma who have not tolerated other therapies or who have refractory or persistent disease. Information provided includes rationale for drug development, study design, efficacy and safety results, and pertinent literature references.  (+info)

Quantitative assessment of myocardial perfusion during graded coronary artery stenoses by intravenous myocardial contrast echocardiography. (63/1663)

OBJECTIVES: The purpose of this study was to examine whether coronary stenoses of variable severity could be quantitatively assessed by analysis of myocardial perfusion as determined by intravenous (IV) myocardial contrast echocardiography. BACKGROUND: Recently, new contrast agents and imaging technology have been developed that may enable improved assessment of myocardial perfusion by IV contrast injection. METHODS: Variable obstruction of the left anterior descending (LAD) coronary artery in dogs was produced by a screw occluder. Coronary artery flow was measured with a transit time flowmeter during baseline, pharmacological vasodilation, a non-flow-limiting stenosis at rest in conjunction with vasodilation, a flow-limiting stenosis, and total occlusion. Myocardial contrast echocardiography was performed after IV injection of the contrast agent NC 100100. Time-intensity curves were obtained off-line for the LAD risk area and the adjacent left circumflex (LCx) territory, and peak background-subtracted video intensity was determined. Fluorescent microspheres were injected at each intervention for determination of regional myocardial blood flow. RESULTS: During non-flow-limiting stenosis, flow limiting stenosis and total occlusion, LAD/LCx ratios of peak myocardial videointensity and blood flow decreased proportionately. Both LAD/LCx ratios of video intensity and blood flow identified the non-flow-limiting and the flow-limiting stenoses as well as total occlusion of the LAD artery. A significant correlation between LAD/LCx video intensity and blood flow ratios was observed (r = 0.83, p < 0.0001). CONCLUSIONS: The degree of blood flow mismatch between ischemic and normal myocardial regions during graded coronary stenoses can be estimated in the dog by quantitative assessment of myocardial perfusion produced by IV myocardial contrast echocardiography.  (+info)

Study of resin-bonded calcia investment: Part 1. Setting time and compressive strength. (64/1663)

This study was carried out to develop a new titanium casting investment consisting of calcia as the refractory material and a cold-curing resin system as the binder. The setting time of the investment was investigated under different N,N-dimethyl-p-toluidine (DMPT) contents in methyl methacrylate monomer (MMA) and benzoyl peroxide (BPO) contents in calcia without any sintering agent. The effects of the sintering agents, which were calcium fluoride (CaF2) and calcium chloride (CaCl2), on the compressive strength of the investments were investigated at room temperature before and after heating to two different temperatures. The shortest setting time (68 minutes) of the investment was obtained at 0.37 DMPT/BPO (1.5 vol% /1.0 mass%) ratio by mass. The highest strength (16.5 MPa) was obtained from the investment which contained 2 mass% CaF2 and was heated to 1,100 degrees C. It was found that the developed calcia investment containing 2 mass% CaF2 has a possibility for use in titanium castings.  (+info)