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At least 991 records · Page 55Linked to original sources
PubMed1994

Enhancement of interstitial photodynamic therapy by mitomycin C and EO9 in a mouse tumour model.

The tumoricidal effect of interstitial photodynamic therapy (IPDT) using Photofrin was found to increase when combined with the bioreductive alkylating agent mitomycin C (MMC) and, to a lesser extent, with the indoloquinone EO9. When MMC was given prior to IPDT or RIF1 tumours, the light dose required for a given regrowth time or for 50% cure was reduced by a factor of 2 compared with IPDT alone. MMC given immediately after illumination did not increase the effects of IPDT, although MMC plus illumination without photosensitizer produced a significant increase in regrowth time compared with MMC or light alone. Combination of IPDT with EO9, given directly before illumination, only marginally increased the tumour regrowth times at non-toxic doses. These results demonstrate that combining IPDT with MMC greatly improves the tumour response. Factors such as PDT-induced hypoxia, pH changes, temperature increases and production of toxic reactive oxygen species by both drugs may play a role in the enhanced MMC cytotoxicity.

Animals↗
PubMed1990

Anionic subsites of the acetylcholinesterase from Torpedo californica: affinity labelling with the cationic reagent N,N-dimethyl-2-phenyl-aziridinium.

Several peptides of acetylcholinesterase of Torpedo californica labelled with the alkylating reagent [3H]N,N-dimethyl-2-phenyl-aziridinium (DPA) were localized within the primary structure. One peptide had the sequence KPQELIDVE (positions 270-278); the incorporation of DPA into this peptide could be specifically suppressed by propidium, which suggests that it is part of the peripheral anionic site. The incorporation of DPA into two other peptides was insensitive to propidium but could be prevented by edrophonium; the sequence of one of the peptides assumed to be part of the anionic site in the catalytic centre was found to be DLFR (positions 217-220). Decamethonium efficiently blocked alkylation by DPA in all three investigated peptides.

Acetylcholinesterase↗
PubMed2004

In vitro culture of rat neuromicrovascular endothelial cells on polymeric scaffolds.

Polyphosphazenes are polymers possessing a skeleton composed of alternating phosphorous and nitrogen atoms, and two side-moieties linked to each phosphorous atom. Polyphosphazenes with amino acid esters as side-moieties are biocompatible and biodegradable polymers. Two polyphosphazenes, poly[bis(ethyl alanate) phosphazene] and poly[(ethyl phenylalanate)0.8(ethyl alanate)0.8(ethyl glycinate)0.4 phosphazene] (PPAGP) were synthesized, and processed to form small fibers. Their ability to support rat neuromicrovascular endothelial cell (EC) adhesion and growth has been studied, using poly(D,L-lactic acid) as reference compound. Scanning electron microscopy revealed that both poly[bis(ethyl alanate) phosphazene] and PPAGP fibers were thinner than poly(D,L-lactic acid) fibers, and possessed a more irregular and porous surface. All polymers increased EC adhesion, compared with polystyrene, but only polyphosphazenes were able to improve EC growth. The highest increase in EC proliferation was induced by PPAGP, which, as revealed by environmental scanning electron microscopy, was also able to induce ECs to arrange into tubular structures. The conclusion is drawn that PPAGP may provide the best scaffold for engineered blood vessels, because it promotes adhesion, growth, and organization of ECs into capillary-like structures.

Animals↗
PubMed2007

Amine-containing core-shell nanoparticles as potential drug carriers for intracellular delivery.

The present study aimed at exploring the use of amine-containing core-shell nanoparticles as potential drug carriers for intracellular delivery. Stable nanoparticles (100-200 nm in diameter) that consisted of poly(methyl methacrylate) (PMMA) cores with hydrophilic poly(ethyleneimine) (PEI) shells were synthesized and used to study their complexation with model drug, ibuprofen (IB), and release it under various electrolyte concentrations. The complexed IB/PEI-PMMA nanoparticles were characterized with FTIR, photon correlation spectroscopy, zeta-potential, and transmission electron microscopy (TEM). Results suggested that the PEI-PMMA nanoparticles could effectively complex with the IB via electrostatic interaction. The thick PEI shells ( approximately 30 nm) significantly enhanced the drug loading capacity up to 23% (w/w) of the complexed nanopartricle. In vitro release of the drug from the complexed nanoparticles was sensitive to the ionic strength of the media. Study of cellular entry of fluorescently labeled IB/nanoparticle complexes using a confocal laser scanning microscopy demonstrated that the entry of the complexed nanoparticles strongly depended on the complexing ratio between IB and PEI-PMMA nanoparticles.

Aziridines↗
PubMed1975

Parthenogenic development after chemical treatment of Xenopus laevis spermatozoa.

Eggs of Xenopus laevis were fertilized in vitro by spermatozoa pre-treated with various concentrations of aziridinyl urea (ethyleneurea) for between 30 and 120 minutes. At 2 and 4 mg/ml for 30 minutes there was a high incidence of abnormal embryos, few of which developed into tadpoles; after 6 and 8 mg/ml no tadpoles were produced. However, the highest concentration 10 mg/ml, yielded 66% of tadpoles, only 7% of which were obviously abnormal. With increasing time the same pattern of events was obtained except for a displacement towards the lower concentration ranges. Tadpoles developing from these latter experiments were found to be haploid. The results resemble those obtained by exposure of Rana pipiens spermatozoa to X-rays and ultraviolet light, with the production of gynogenetic embryos, usually referred to as the Hertwig effect.

Animals↗
PubMed2005

Towards gene therapy in prosthesis loosening: efficient killing of interface cells by gene-directed enzyme prodrug therapy with nitroreductase and the prodrug CB1954.

BACKGROUND: Loosening is a major complication in prosthesis surgery. To stabilize loosened orthopedic implants, the interface tissue surrounding the implant must be removed. As an alternative to manual removal, we explored the possibility of removing the tissue by gene-directed enzyme prodrug therapy. In the current study we investigated whether interface cells can be transduced by an HAdV-5 vector carrying the E.coli-derived nitroreductase gene and sensitized to the prodrug CB1954. METHODS: The gene transfer efficiency into cultures of diploid human interface cells was tested by exposing these cells to various concentrations of Ad.CMV.LacZ. Subsequently, we studied the susceptibility of cells to the NTR/CB1954 combination. RESULTS: X-gal staining of the Ad.CMV.LacZ-transduced cell cultures revealed that, at 200 plaque-forming units (pfu)/cell, 74% of the cells expressed the LacZ gene. Infection with an NTR construct in interface cell lines resulted in a 60-fold sensitization to the prodrug CB1954. In addition we observed that iotrolan (Isovist) contrast medium had no effect on viability of the cells. However, the presence of the contrast medium completely inhibited adenovirus-mediated gene transfer. CONCLUSIONS: From these data we conclude that HAdV-5-based vectors carrying nitroreductase can be used to sensitize interface tissue. Instead of contrast medium the clinical protocol will use an alternative visualization procedure.

Adenoviridae↗
PubMed2006

Quantitative analysis of EO9 (apaziquone) and its metabolite EO5a in human plasma by high-performance liquid chromatography under basic conditions coupled to electrospray tandem mass spectrometry.

A sensitive and specific LC-MS/MS assay for the quantitative determination of EO9 and its metabolite EO5a is presented. A 200-microl human plasma aliquot was spiked with a mixture of deuterated internal standards EO9-d3 and EO5a-d4 and extracted with 1.25 ml ethyl acetate. Dried extracts were reconstituted in 0.1 M ammonium acetate-methanol (7 : 3, v/v) and 25 microl-volumes were injected into the HPLC system. Separation was achieved on a 150 x 2.1 mm C18 column using an alkaline eluent (1 mM ammonium hydroxide-methanol (gradient system)). Detection was performed by positive ion electrospray followed by tandem mass spectrometry. The assay quantifies a range from 5 to 2500 ng/ml for EO9 and from 10 to 2500 ng/ml EO5a using 200 microl of human plasma samples. Validation results demonstrate that EO9 and EO5a concentrations can be accurately and precisely quantified in human plasma. This assay will be used to support clinical pharmacologic studies with EO9.

Antineoplastic Agents, Alkylating↗
PubMed2004

Cytomegalovirus antiviral resistance associated with treatment induced UL97 (protein kinase) and UL54 (DNA polymerase) mutations.

HCMV-related illness due to infections with antiviral resistant virus was verified by phenotypic and genotypic assays in 17% (8/47) of high-risk immunocompromised Australian patients. Selective PCR-sequencing of UL97 (protein kinase; PK) and UL54 (DNA polymerase; DNApol) regions important for antiviral sensitivity, identified the majority (6/8) of resistant strains through detection of mutations known to confer antiviral resistance. Additionally, eight UL54 (DNApol) mutations (N408K, T691S, A692V, S695T, L737M, A834P, V955I, and A972V) of unknown phenotype were identified in six specimens from patients with clinical evidence of antiviral resistant infections. One isolate was resistant to ganciclovir (GCV) and another resistant to PFA on phenotypic testing where mutations in UL97 (PK) or UL54 (DNApol) were not detected, suggesting a loss of correlation between phenotype and genotype. Selective PCR-sequencing of UL97 (PK) and UL54 (DNApol) provided rapid and comprehensive results, but missed some resistance detected by phenotypic assays. A combination of phenotypic and genotypic assays is recommended for complete analysis of CMV antiviral resistance, as well as further definition of the clinical relationship between novel UL54 (DNApol) mutations and antiviral resistance.

Amino Acid Substitution↗
PubMed1981

2,5-Diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone I: Kinetics in aqueous solutions by high-performance liquid chromatography.

The application of a rapid, selective, and sensitive reversed-phase high-performance liquid chromatographic method to the analysis of 2,5-diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone (I) and its degradation products is described. The method was used to study the kinetics of degradation of I over pharmaceutically useful pH ranges. The overall reaction rate followed pseudo-first-order kinetics. The pH-rate profile demonstrated optimal stability between pH 6.0 and 6.5. The degradation behavior suggests the existence of multiple pathways. The temperature dependence of th disappearance of I also was evaluated from the regression equation derived from the Arrhenius plot.

Antineoplastic Agents↗
PubMed1987

Treatment of lymphohistiocytic erythrophagocytosis with VP-16 and aziridinylbenzoquinone.

Lymphohistiocytic erythrophagocytosis (LE) is a usually fatal disease characterized by fever, organomegaly, hyperlipidemia, central nervous system involvement, and cellular immunodeficiency. Treatment with corticosteroids, cytotoxic chemotherapy, and blood exchange is unsuccessful. We have treated two children with the epipodophyllotoxin VP-16 and with intrathecal chemotherapy. Each patient had an initial complete response, and one remains in remission 36 months after therapy began. Aziridinylbenzoquinone (AZQ) therapy induced a complete response in a patient who relapsed during VP-16 therapy. A combination of VP-16 and intrathecal chemotherapy appears to be the most effective therapy for LE, and further evaluation of the role of AZQ is indicated.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1982

Factors influencing the severity and progress of ethylenimine-induced papillary necrosis.

The severity of the renal papillary necrosis produced in rats by ethylenimine is dependent both on dose and urinary concentration within the medulla. When this is reduced by diuresis, the severity of the lesion is effectively reduced. Increasing urinary concentration has a reverse effect, but of less magnitude. When the concentrating power of the renal medulla is impaired by a single dose of ethylenimine, insufficient to cause necrosis of the whole papilla, further doses of ethylenimine do not cause progressive damage to the papilla.

Ammonium Chloride↗
PubMed2001

Consecutive carbon-carbon bond formation approach in tandem cyclization reactions.

The conventional tandem cyclization reactions involve the formation of alternating carbon-carbon bonds, whereas the newly developed cyclization reactions involve the formation of consecutive carbon-carbon bonds, in which N-aziridinylimines have been utilized as geminal radical acceptor and donor equivalents in a single operation. This unprecedented tandem cyclization approach becomes feasible by the successful generation of 5- and 6-membered ring radicals by radical cyclizations of N-aziridinylimines. The same notion can be applied to the anionic cyclizations of N-aziridinylimines, thereby allowing anionic consecutive carbon-carbon bond formation. This approach has great synthetic potential, particularly for the construction of quaternary carbon centers, and it provides highly efficient routes for the synthesis of natural products.

Aziridines↗
PubMed1996

Spermine binding to GC-rich DNA: experimental and theoretical studies.

The DNA binding of spermine has been studied using experimental and computational approaches. Spermine blocks 5'-GC interstrand crosslinking by 2,5-diaziridinylbenzoquinone in the oligonucleotide duplex 5'-CTTCCAAGATGCATCAGATG 5'-CATCTGATGCATCTTGGAAG (where the underlined nucleotide bases represent the crosslinking site). Molecular dynamics simulations suggest that this is a result of preferential spermine binding at the 5'-GC major groove site of the oligonucleotide. A further simulation with a GC-alternating sequence shows a similar preference for the 5'-GC step. In a simulation including multiple spermine molecules, occupation of alternate 5'-GC steps occurred. From this, we deduced a mechanism for the experimentally observed cooperativity of spermine binding to poly(dGdC)2.

Aziridines↗
PubMed1997

Molecular analysis of carotenoid cyclase inhibition.

Later steps of carotenoid biosynthesis catalyzed by cyclase enzymes involve the formation of alpha, beta, and kappa-rings. Examination of the primary structure of lycopene beta-cyclase revealed 55% identity with that of antheraxanthin kappa-cyclase. Recombinant lycopene beta-cyclase afforded only beta-carotene, while recombinant antheraxanthin kappa-cyclase catalyzed the formation of beta-carotene from lycopene as well as the conversion of antheraxanthin into the kappa-carotenoid capsanthin. Since the formation of beta- and kappa-rings involves a transient carotenoid carbocation, this suggests that both cyclases initiate and/or neutralize the incipient carbocation by similar mechanisms. Several amine derivatives protonated at physiological pH were used to examine the molecular basis of this phenomenon. The beta-and kappa-cyclases displayed similar inhibition patterns. Affinity or photoaffinity labeling using p-dimethylamino-benzenediazonium fluoroborate, N,N-dimethyl-2-phenylaziridinium, and nicotine irreversibly inactivated both cyclase enzymes. Photoaffinity labeling using [3H]nicotine followed by radiosequence analysis and site-directed mutagenesis revealed the existence of two cyclase domains characterized by the presence of reactive aromatic and carboxylic amino acid residues. We propose that these residues represent the "negative point charges" involved in the coordination of the incipient carotenoid carbocations.

Affinity Labels↗