Anthracyclines such as doxorubicin remain among the most effective agents for the treatment of solid tumors and hematological malignancies. To overcome dose-limiting side effects like cardiotoxicity, an intensive effort has been undertaken to develop promising doxorubicin prodrugs that are specifically activated at the tumor site. One approach is the application of peptide prodrugs of doxorubicin. The enzyme cathepsin B catalyzes the activation of these prodrugs, and hence, the regulation of cathepsin B by antitumor agents could influence the efficacy of peptide prodrugs using this protease. In the present investigation, the effects of doxorubicin on cathepsin B expression in the human cervix carcinoma cell line HeLa were examined. Exposure to doxorubicin induced a time-and dose-dependent up-regulation of cathepsin B expression on mRNA, protein, and activity levels. In the cathepsin B gene promoter region, a potential nuclear factor B (NF-B) binding site could be identified. Pretreatment of HeLa cells with specific NF-B inhibitors abrogated the induction of cathepsin B expression. Doxorubicin-induced degradation of the inhibitory protein IB could be prevented by pretreatment with a specific proteasome inhibitor, resulting in a significant reduction of the doxorubicininduced cathepsin B expression. Finally, binding of NF-B subunits p50 and p65 to the NF-B binding site in the cathepsin B gene promoter region could be demonstrated by electrophoretic mobility shift assay. In summary, our data clearly indicate that doxorubicin induces cathepsin B expression and activity via NF-B. These findings contribute to a better understanding of tumor targeting with peptide prodrugs and help to define a possible mechanism of doxorubicin toxicity in tumor cells.
The deleterious consequences of total beta-glucuronidase deficiency, leading to symptomatic mucopolysaccharidosis type VII (MPS VII), have been firmly established. However, the question of whether sequence variations in beta-glucuronidase of non-MPS VII patients affect expression of the enzyme, thereby explaining the wide inter-individual expression, has not been addressed in a systematic manner. In the present study, a population of 965 subjects were screened for enzyme activity and relevant fractions of the beta-glucuronidase gene were sequenced in those individuals belonging to the highest or lowest decile of activity. The study showed a substantial inter-individual variability of beta-glucuronidase in plasma (range 0.5-150.2 micromol/min) and confirmed the association of beta-glucuronidase activity with gender (P < 0.001), age (r = 0.218; P < 0.001) and body mass index (r = 0.311; P < 0.001). We were able to identify six beta-glucuronidase single base substitutions (-1026A > G, -72G > T, -12G > A, +7728C > T, +14 209C > T and +14 604A > G) in 193 non-MPS VII patients at a rate of one single nucleotide polymorphism (SNP) per 520 bp sequenced. The GG genotype of +14 604A > G and the CT genotype of +14 209C > T were associated with higher beta-glucuronidase activity (P < 0.05). Subsequently, reporter gene assays were carried out to elucidate the effects of the SNPs -1026A > G, -72G > T and -12G > A, and the combined genotype -1026A > G and -12G > A observed in one of the subjects. Variant -12G > A reduced the promoter activity (75%; 95% confidence interval 70-84%, P < 0.05). The present study demonstrates that three of the described SNPs influence the activity and/or expression of beta-glucuronidase. Taken together, the data indicate a rather limited influence of genetic factors on inter-individual variability in beta-glucuronidase activity.
Laser-induced fluorescence (LIF) spectroscopy in combination with fiber optics is shown to be a powerful tool for qualitative and quantitative diagnostics of environmental pollutants in water and soil. Timeintegrated data accumulation of the LIF signals in early and late time windows with respect to the excitation pulse simplifies the method so that it becomes attractive for practical applications. Results from field measurements are reported, as oil contaminations under a gas station and in an industrial sewer system are investigated. A KrF-excimer laser and a hydrogen Raman shifter can be applied for multiwavelength excitation. This allows a discrimination between benzene, toluene, xylene, and ethylbenzene aromatics and polycyclic aromatic hydrocarbon molecules in the samples under investigation. For a rough theoretical approach, a computer simulation is developed to describe the experimental results.
Coronary angiography using laser plasma sources: X-ray source efficiency and optimization of a bent crystal monochromatorAndersson, E; Holzer, G; Forster, E; Gratz, M; Kiernan, L; Sjogren, A; Svanberg, Sune Andersson, E., Holzer, G., Forster, E., Gratz, M., Kiernan, L., Sjogren, A., & Svanberg, S. (2001). Coronary angiography using laser plasma sources: X-ray source efficiency and optimization of a bent crystal monochromator. Applied Physics Reviews, 90(6), 3048-3056. DOI: 10.1063/1.1394904General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Coronary angiography using laser plasma sources: X-ray source efficiency and optimization of a bent crystal monochromator A monochromator has been developed for coronary angiography, comprising a single bent crystal of silicon in Laue transmission geometry. K spectra of laser irradiated solid tin and tantalum ͑Zϭ50 and 73, respectively͒ targets were measured. The high resolution crystal spectrometer resolve the Sn and Ta K␣ doublets, allowing in a proof-of-principle experiment the absolute K␣ photon numbers emitted by the source to be determined. The Ta K␣ yield is measured as a function of the laser pulse energy, allowing an assessment to be made of the suitability of such sources for medical applications.
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