Synthesis, cellular uptake and animal toxicity of a tetra(carboranylphenyl) -tetrabenzoporphyrin

A water-soluble nido-carboranyl-tetrabenzoporphyrin has been synthesized in 43% overall yield, by condensation of butanopyrrole with a carboranylbenzaldehyde, followed by metal insertion, oxidation, demetallation and deboronation reactions. This compound accumulated within human glioblastoma T98G cells to a significant higher extent than a structurally related nido-carboranylporphyrin, and localized preferentially in the cell lysosomes. Animal toxicity studies using male and female BALB/c mice revealed that both compounds are non-toxic even at a dose of 160 mg/kg, administered intraperitoneally as a single injection at a concentration of 4 mg/mL. It is concluded that the tetra(carboranylphenyl)-tetrabenzoporphyrin is a promising new sensitizer for the treatment of malignant tumors. © 2005 Elsevier Ltd. All rights reserved

Effects of extracorporeal shock wave therapy on desmitis of the accessory ligament of the deep digital flexor tendon in the horse

OBJECTIVE: To evaluate the effects of extracorporeal shock wave therapy (ESWT) on collagenase-induced lesions in the accessory ligament of the deep digital flexor tendon (ALDDFT) of horses. STUDY DESIGN: Paired, blinded controlled study. ANIMALS: Eight Thoroughbred horses (3 mares, 5 geldings; mean ± SD weight, 464 ± 26 kg, mean age, 8 ± 1.7 years). METHODS: Lesions were created in both ALDDFTs of all horses by injection of 2 × 10(3) IU of collagenase type I. Percent lesion and structure (fiber alignment and echogenicity) were quantified with ultrasonographic imaging 3, 6, and 9 weeks after collagenase injection. After ultrasound examinations, ESWT (1000 shocks at 0.15 mJ/mm2) was applied to 1 ALDDFT in each horse. ALDDFT were harvested 15 weeks after collagenase injection and the microstructure, mRNA levels of collagen types I and III, and collagen and glycosaminoglycan content were evaluated. RESULTS: There were no differences in percent lesion, echogenicity, or fiber alignment between control- and ESWT-treated ligaments at each evaluation time; however, compared with 3-week values, there was a significant increase in percent lesion and echogenicity for EWST treated ligaments at 6 weeks and significant decrease in both variables for treated and control ligaments at 12 weeks. Fiber alignment improved significantly at 9 weeks in controls and at 12 weeks in treated and control ligaments. Collagen type I mRNA levels were significantly higher in the ESWT treatment group compared with the control group 15 weeks after collagenase injection though differences in other mRNA levels, microstructure, and composition were not significant. CONCLUSIONS: Our results do not support an effect of ESWT on collagenase-induced lesions in the equine ALDDFT

Effective treatment of human breast tumor in a mouse xenograft model with herpes simplex virus type 1 specifying the NV1020 genomic deletion and the gBsyn3 syncytial mutation enabling high viral replication and spread in breast cancer cells

A new oncolytic and fusogenic herpes simplex virus type 1 (HSV-1) was constructed on the basis of the wildtype HSV-1(F) strain. To provide for safety and tumor selectivity, the virus carried a large deletion including one of the two α4, γ134.5, α0 genes and the latency-associated transcript region. The γ134.5 gene, a major neurovirulence factor, was replaced by a gene cassette constitutively expressing the red fluorescent protein gene. Homologous recombination was used to transfer the fusogenic gBsyn3 mutation to the viral genome to produce the OncSyn virus. OncSyn causes extensive virus-induced cell fusion (syncytia) and replicates to higher titers than the parental One and HSV-1(F) strains in breast cancer cells. Biochemical analysis revealed that the OncSyn virus retains a stable genome and expresses all major viral glycoproteins. A xenograft mouse model system using MDA-MB-435S-luc (MM4L) human breast cancer cells constitutively expressing the luciferase gene implanted within the interscapular region of animals was used to test the ability of the virus to inactivate breast tumor cells in vivo. Seventy-two mice bearing MM4L breast cancer xenografts were randomly divided into three groups and given two rounds of three consecutive intratumoral injections of OncSyn, inactivated OncSyn, or phosphate-buffered saline 3 days apart A single round of virus injections resulted in a drastic reduction of tumor sizes (p ≤ 0.0001) and diminution of chemiluminescence emitted by the cancer cells (p ≤ 0.0002). This effect was enhanced by a second round of virus injections into the tumors 3 days after the first round (p ≤ 0.0001). Systematic necropsy and pathological evaluation of the primary tumors revealed that the single round of injections resulted in extensive necrosis of tumor cells (p ≤ 0.0001), which was enhanced by the second round of injections (p ≤ 0.0002). Internal organs were not affected by virus inoculation. Mouse weights were not significantly impacted by any treatment during the course of the entire study (p = 0.46). These results show that the attenuated, fusogenic, and oncolytic HSV-1(F) virus strain OncSyn may effectively treat human breast tumors in vivo. © Mary Ann Liebert, Inc

Sediment from Hurricane Katrina: Potential to Produce Pulmonary Dysfunction in Mice

On August 29, 2005, Hurricane Katrina made landfall along the Gulf Coast as a Category 3 hurricane. The associated storm surge and heavy rainfall resulted in major flooding throughout the New Orleans area. As the flood waters receded, thick sediment was left covering the ground and coating the interior of homes. This sediment was dispersed into the air and inhaled as dust by returning residents and workers. Our objective in this study was to evaluate the potential pulmonary effects associated with the respirable particulate matter (PM) derived from Hurricane Katrina (HK-PM) in mice. Samples of PM were collected from several locations along the Gulf Coast on September 30 and October 2, 2005 and had a mean aerodynamic diameter ranging from 3-5 μm). Chemical analysis and cytotoxicity assays were performed for all HK-PM samples. A few samples with varying levels of cytotoxicity were chosen for an acute inhalation exposure study. Airborne PM10 levels recorded in the New Orleans area post-Katrina were variable, ranging from 70 μg/m3 in Gentilly to 688 μg/m3 in Lakeview (residential areas). Mice exposed to one of these samples developed significant pulmonary inflammation and airways resistance and hyperresponsiveness to methacholine challenge. These studies demonstrate that dispersion of certain Katrina sediment samples through either natural (e.g., wind) or mechanical (e.g., vehicles) processes promotes airflow obstruction in mice