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1.
Kappus H. Kieczka H. Scheulen M. Remmer H. 《Naunyn-Schmiedeberg's archives of pharmacology》1977,300(2):179-187
Summary Lipid peroxidation was induced in rat liver microsomes either by iron-ADP-complexes or by carbon tetrachloride in the presence of NADPH. Different compounds containing catechol or pyrogallol structures were examined for their activities to inhibit lipid peroxidation in both systems. In general, all compounds tested showed similar inhibitory activities on lipid peroxidation, if induced by ferrous ion-ADP-complexes or by carbon tetrachloride. This inhibition is explained by the suggestion that catechols and pyrogallos inhibit at the lipid site of the membrane, rather than at the enzymic site. Compounds not containing catechol or pyrogallol groups inhibited lipid peroxidation only weakly. O-Methylation resulted in a decrease of the inhibitory effect. Catecholor pyrogallol-derivatives which contained polar functional side chains, like carboxyl- or amino groups showed minor inhibitory effects compared to the esterified or N-alkylated compounds.Dihydroxychlorpromazine, 2-hydroxy-estradiol and 2-hydroxyethinylestradiol were the most effective inhbitors of microsomal lipid peroxidation (I50-values of 1×10–6 to 2×10–7 M). The inhibitory activity of -tocopherol, glutathione and ascorbic acid, naturally occurring antioxidants, was about three orders of magnitude lower.Inhibition of lipid peroxidation induced by NADPH-cytochrome c reductase and iron-ADP-complexes in the presence of NADPH and liposomes was also observed with catechols.From our results we assume that the molecular structure of a catechol or pyrogallol functional group is a prequisite for an effective inhibition of lipid peroxidation by these chemicals. Furthermore, the results are discussed in relation to the requisite membrane affinity of catechols, pyrogallols and other antioxidants which might be used for inhibition studies on lipid peroxidation in vivo. 相似文献
2.
When rats were dosed with 14 g/kg 3H-isoproterenol, 3H-radioactivity was measurable in the liver until 48 h. This amount was not different in livers of animals which have been pretreated with diethyl maleate.After exhaustive extraction, a significant amount of 3H-radioactivity from isoproterenol could be detected in the proteins of total liver (homogenate), of cytosol and of microsomes. In the cytosol fraction of diethyl maleate pretreated animals twice the amount of isoproterenol-radioactivity was found in the extracted proteins compared to controls. In the microsomal fraction there was no difference between diethyl maleate pretreated and control animals in the amount of radioactivity incorporated into proteins.In all fractions the radioactivity measurable in the extracted proteins declined with a half life time of about 24 h.The in vivo results on covalent binding of isoproterenol are compared to the irreversible protein binding of ethinyloestradiol in vivo. Quantitatively, these in vivo data are compared to the results on irreversible protein binding obtained during incubations of isoproterenol or ethinyloestradiol with rat liver microsomes.Presented at the Symposium Influence of Metabolic Activations and Inactivations on Toxic Effects held at the 18th Spring Meeting of the Deutsche Pharmakologische Gesellschaft, Section Toxicology, D-6500 Mainz, March 15, 1977 相似文献
3.
Cytokines are part of pathogenesis in many diseases. Their measurement could be interesting for diagnostic purposes. One cytokine which participates in different inflammatory and neoplastic diseases is interleukin-6 (IL-6). The aim of this study was to investigate the IL-6 serum concentration in dogs with different liver diseases to show if there is any association between the cytokine serum level and the disease aetiology or the degree of the disease. IL-6 was measured in dogs with acute hepatitis, chronic hepatitis of different degrees and primary and secondary liver tumours. The data were compared with clinically healthy dogs and dogs with extra-hepatic diseases. For measurement, a commercial ELISA Kit (R&D Systems) was used. Compared with clinically healthy dogs and dogs with diabetes mellitus, all dogs with an intra- or extra-hepatic inflammatory or neoplastic disease have increased serum levels of IL-6. Dogs with acute hepatitis have significantly increased IL-6 serum concentrations compared with dogs with chronic hepatitis (P?<?0.05). No significant difference between mild and moderate chronic hepatitis exists (P?>?0.05). Dogs with secondary liver tumours have significantly increased IL-6 serum concentrations in comparison to dogs with primary liver tumours (P?<?0.01), but both groups have comparable IL-6 serum concentration to dogs with extra-hepatic tumours. Measurement of IL-6 serum concentration may help differentiate between acute and chronic hepatitis and between primary and secondary liver tumours. Further information about the aetiology of the liver disease cannot be obtained by measuring IL-6 in the serum. 相似文献
4.
Kasimir-Bauer S Beelen D Flasshove M Noppeney R Seeber S Scheulen ME 《Experimental hematology》2002,30(11):1302-1308
OBJECTIVE: Resistance to chemotherapy-induced apoptosis and a multidrug-resistance phenotype is the major problem in the treatment of acute myeloid leukemia (AML). PATIENTS AND METHODS: We recently demonstrated that the coexpression of at least two proteins, including P glycoprotein, multidrug resistance-related protein, bcl-2 (flow cytometry), p53 (luminometric immunoassay), and heat shock protein 27 (Western blotting), was predictive for response to induction therapy in de novo AML comparing leukemic blasts of 20 responders with 20 nonresponders. After long-term follow-up, we now present our evaluation on the prognostic significance of these proteins in leukemic blasts of 124 untreated AML patients with regard to the probability of remission (PoR) and overall survival (OS). RESULTS: Analyzing leukemic blasts obtained from bone marrow samples, we found that no single protein significantly correlated with PoR or OS. In contrast, the coexpression of at least two of these proteins was predictive for reduced OS in univariate as well as multivariate analysis. Although we could not identify any particular protein combination predictive for reduced OS, those patients with no or only one protein expressed in their leukemic blasts had a survival probability of 48% in contrast to 24% in those patients with the coexpression of two or more proteins. Among the clinical markers, only response to chemotherapy had a significant effect on OS and age was of prognostic relevance for PoR. CONCLUSION: We conclude that overexpression of only one protein possibly involved in resistance, is not sufficient to influence the prognosis for long-term survival in AML, whereas the expression of more than one protein is predictive for reduced OS. Protein combination seems to be individually different, and targeting only one protein in further clinical trials may not help to overcome multifactorial resistance. 相似文献
5.
Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors. 总被引:4,自引:0,他引:4
H Richly B F Henning P Kupsch K Passarge M Grubert R A Hilger O Christensen E Brendel B Schwartz M Ludwig C Flashar R Voigtmann M E Scheulen S Seeber D Strumberg 《Annals of oncology》2006,17(5):866-873
BACKGROUND: Sorafenib (BAY 43-9006), a novel, oral multi-kinase inhibitor, blocks serine/threonine and receptor tyrosine kinases in the tumor and vasculature. Sorafenib demonstrated single-agent activity in Phase I studies, and was tolerated and inhibited tumor growth in combination with doxorubicin in preclinical studies. This Phase I dose-escalation study determined the safety, pharmacokinetics and efficacy of sorafenib plus doxorubicin. PATIENTS AND METHODS: Thirty-four patients with refractory, solid tumors received doxorubicin 60 mg/m(2) on Day 1 of 3-week cycles, and oral sorafenib from Day 4 of Cycle 1 at 100, 200 or 400 mg bid. RESULTS: Common drug-related adverse events were neutropenia (56%), hand-foot skin reaction (44%), stomatitis (32%), and diarrhea (32%). The maximum tolerated dose was not reached. One patient with pleural mesothelioma achieved a partial response (modified WHO criteria) and remained on therapy for 39.7 weeks. Fifteen patients (48%) achieved stable disease for >/=12 weeks. Doxorubicin exposure increased moderately with sorafenib 400 mg bid. The pharmacokinetics of sorafenib and doxorubicinol were not affected. CONCLUSION: Sorafenib 400 mg bid plus doxorubicin 60 mg/m(2) was well tolerated. The increased doxorubicin exposure with sorafenib 400 mg bid did not result in significantly increased toxicity; low patient numbers make the clinical significance of this unclear. These promising efficacy results justify further clinical investigation. 相似文献
6.
7.
Pieck AC Drescher A Wiesmann KG Messerschmidt J Weber G Strumberg D Hilger RA Scheulen ME Jaehde U 《British journal of cancer》2008,98(12):1959-1965
In this study, we investigated the kinetics of oxaliplatin-DNA adduct formation in white blood cells of cancer patients in relation to efficacy as well as oxaliplatin-associated neurotoxicity. Thirty-seven patients with various solid tumours received 130 mg m(-2) oxaliplatin as a 2-h infusion. Oxaliplatin-DNA adduct levels were measured in the first cycle using adsorptive stripping voltammetry. Platinum concentrations were measured in ultrafiltrate and plasma using a validated flameless atomic absorption spectrometry method. DNA adduct levels showed a characteristic time course, but were not correlated to platinum pharmacokinetics and varied considerably among individuals. In patients showing tumour response, adduct levels after 24 and 48 h were significantly higher than in nonresponders. Oxaliplatin-induced neurotoxicity was more pronounced but was not significantly different in patients with high adduct levels. The potential of oxaliplatin-DNA adduct measurements as pharmacodynamic end point should be further investigated in future trials. 相似文献
8.
Schultheis B Strumberg D Bergmann L Graeven U Hanauske AR Lipp R Schuette J Saito K Scigalla P Scheulen ME 《Investigational new drugs》2012,30(3):1184-1192
Purpose S-1, an oral fluoropyrimidine derivative, has previously demonstrated anticancer efficacy in pancreatic cancer (PC), predominantly
in Asian populations. This study evaluated the antitumor effect and safety of S-1 in Caucasian patients with metastatic PC.
Methods Chemotherapy-na?ve patients received S-1 orally at 30 mg/m2 twice daily (BID) for 2 weeks, repeated every 3 weeks. Primary endpoint was ORR. Secondary endpoints included PFS, OS and
safety assessment. The trial had a Simon’s two-stage design with 22 patients evaluable for efficacy in stage 1 and an additional
18 patients in stage 2, if ≥3/22 patients had a confirmed response at the first stage. Results Three out of 27 patients showed PR, however, detection of asymptomatic brain metastases in one of them prevented this study
from proceeding to stage 2. The median PFS and OS for all patients was 3.5 and 9.1 months, respectively. The median duration
of disease control for patients with SD or PR (n = 17) was 4.3 months. S-1 was well tolerated; fatigue was the most frequent grade 3/4 adverse event. Conclusions Efficacy data of PFS and OS are at least comparable to gemcitabine, the current standard of care. S-1 is active in Caucasian
patients with metastatic PC. 相似文献
9.
Aerobic incubations of bleomycin, FeCl3, DNA, NADPH, and isolated liver microsomal NADPH-cytochrome P-450 reductase resulted in NADPH and oxygen consumption and malondialdehyde formation, indicating that the deoxyribose moiety of DNA was split. All parameters measured depended on the active enzyme, bleomycin and FeCl3. In the absence of oxygen malondialdehyde formation was very low.When bleomycin, FeCl3 and the reductase were incubated with methional ethene (ethylene) was formed, suggesting that during the enzyme-catalyzed redox cycle of bleomycin-Fe(III/II) hydroxyl radicals were formed. Ethene formation also depended on oxygen, NADPH, the enzyme, bleomycin, and FeCl3.During aerobic incubations of bleomycin, FeCl3, NADPH, and isolated liver nuclei oxygen and NADPH were consumed and malondialdehyde was formed. Oxygen and NADPH consumption and malondialdehyde formation depended on bleomycin and FeCl3. In the absence of oxygen malondialdehyde was not formed. These results indicate that nuclear NADPH-cytochrome P-450 reductase redox cycles the bleomycin-Fe(III/II) complex and that the reduced complex activates oxygen, whereby hydroxyl radicals are formed which damage the deoxyribose of nuclear DNA.Dedicated to Professor Dr. med. Herbert Remmer on the occasion of his 65th birthday 相似文献