The mechanism of tumor cell killing by OXI4503 was investigated by studying vascular functional and morphological changes post drug administration. SCID mice bearing MHEC5-T hemangioendothelioma were given a single dose of OXI4503 at 100 mg/kg. Tumor blood flow, measured by microsphere fluorescence, was reduced by 50% at 1 hr, and reached a maximum level 6 -24 hr post drug treatment. Tumor vascular permeability, measured by Evan's blue and hemoglobin, increased significantly from 3 hr and peaked at 18 hr. The elevated tumor vessel permeability was accompanied by an increase in vascular endothelial growth factor (VEGF) from 1 hr post drug treatment. Immunohistochemical staining for CD31 and laminin showed that tumor blood vessels were affected as early as 3 hr but more prominent from 6 hr. From 12 hr, the vessel structure was completely destroyed. Histopathological and double immunohistochemical staining showed morphological change and induction of apoptosis in endothelial cells at 1-3 hr, followed by tumor cell necrosis from 6 -72 hr. There were no statistically significant changes of Evan's blue and hemoglobin contents in liver tissue over the time course. These results suggest that OXI4503 selectively targets tumor blood vessels, and induces blood flow shutdown while it enhances tumor blood vessel permeability. The early induction of endothelial cell apoptosis leads to functional changes of tumor blood vessels and finally to the collapse of tumor vasculature, resulting in massive tumor cell necrosis. The time course of the tumor vascular response observed with OXI4503 treatment supports this drug for development as a stand alone therapy, and also lends support for the use of the drug in combination with other cancer therapies.

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The natural products colchicine and combretastatin A-4 (CA4) are potent inhibitors of tubulin assembly, and they have inspired the design and synthesis of a large number of small-molecule, potential anticancer agents. The indole-based molecular scaffold is prominent among these SAR modifications, leading to a rapidly increasing number of agents. The water-soluble phosphate prodrug 33 (OXi8007) of a 2-aryl-3-aroylindole-based phenol 8 (OXi8006) was prepared by chemical synthesis and found to be strongly cytotoxic against selected human cancer cell lines (GI50 = 36 nM against DU-145 cells, for example). The free phenol, 8 (OXi8006), was a strong inhibitor (IC50 = 1.1 µM) of tubulin assembly. The corresponding phosphate prodrug 33 (OXi8007) also demonstrated pronounced interference with tumor vasculature in a preliminary in vivo study utilizing a SCID mouse model bearing an orthotopic PC-3 (prostate) tumor as imaged by color Doppler ultrasound. The combination of these results provides evidence that the indole-based phosphate prodrug 33 (OXi8007) functions as a vascular disrupting agent (VDA) that may prove useful for the treatment of cancer.

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The early stages of the formation of the Au-Si interface have been studied with photoelectron spectroscopy of the valence-band and core levels. In this study, the Si sample was prepared by cleavage in ultrahigh vacuum and Au was deposited in a controlled manner at room temperature, By slowly increasing the Au coverage on the surface, the silicon surface states were depleted rapidly (by a factor of 2 at an Au coverage of 0.2 monolayers) without any observable change ()0.1 eV) in the Fermi-level pinning position. Furthermore, at low coverages, the binding energies of the Au core levels and the Sd peaks in the valence band were similar to those of atomic Au; however, the width of the structure indicated that the Au is strongly interacting with Si. Measurement of the strength of the Au core levels gives evidence for penetration of a fraction of Au into Si. Thus, at low coverages, the Au is probably dispersed in and on the Si, causing the removal of the surface states and production of new states in the band gap. As the Au coverage is increased, the Au 4f and Si 2p core levels shift in such a way as to suggest the formation of an alloy with variable composition at the Au-Si interface. At the highest Au coverages {above 15 monolayers), a small amount (less than 1 monolayer) of Si was observed on the surface of the deposited Au overlayer. Thermal annealing of a thin Au (50 monolayers of Au) on Si at 500'C resulted in an increased Si concentration at the surface with the photoelectron spectra resembling those at low coverages (about 1.5 monolayers), thus indicating a high diffusion coefficient of Si through the Au layer. When less than 1 monolayer of 02 was adsorbed onto the cleaved Si surface prior to the deposition of Au, the intermixing of Au and Si was significantly reduced,

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There were no statistically significant differences in mortality rates among TA, RP, and EV. Respiratory failure was significantly more common after TA repair, compared with RP or EV, whereas wound complications were more common after RP. Overall cost was significantly higher for TA repair, with no significant difference in cost between EV and RP. EV repair significantly shortened hospital stay and intensive care unit (ICU) use and had a lower morbidity rate. Cost savings in LOS were significantly reduced in the EV group by the increased cost of supplies and radiology, accounting for a similar cost between EV and RP. Considering the increased resource use preoperatively and during follow-up for EV patients, the difference in cost between TA and EV may be insignificant. EV repair is unlikely to save money for the health care system; its use is likely to be driven by patient and physician preference, in view of a significant decrease in the morbidity rate and length of hospital stay.

No abstract