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  • 1
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The purpose of this study was to determine whether changes in cellular lipid composition accompanied the selection of cells that are resistant to the anthracycline doxorubicin. Total cellular lipid extracts from doxorubicin-sensitive and doxorubicin-resistant P388 murine leukemia cells were prepared and separated into neutral glycosphingolipids, gangliosides, phospholipids, and neutral lipid families. No significant quantitative differences in total cholesterol, lipid-bound sialic acid, neutral hexose, and lipid-bound phosphate were found between the two cell lines. Gas-liquid chromatographic analysis of the fatty acids derived from each lipid class demonstrated that sensitive and resistant cells had essentially identical fatty acid compositions. Qualitative evaluation of the four lipid classes by high-performance thin layer chromatography revealed only minor differences in lipid composition between the resistant and the sensitive cells. Results from this study indicate that although minor differences between the two cell lines are present, no major cellular lipid differences are evident to account for the marked differences in the cellular pharmacokinetics and cytotoxic effects of doxorubicin between doxorubicin-sensitive and doxorubicin-resistant P388 murine leukemia a cells.
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  • 2
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pharmacokinetic behavior of carboplatin administered by the i.p. route at a dose of 200 mg/m2 was studied during five courses of therapy in four patients with ovarian cancer. A regional pharmacologic advantage was noted with carboplatin administered by this route, with (1) peak peritoneal fluid concentrations 18-fold those in plasma, and (2) area under the curve (AUC) for the peritoneum showing a 18-fold and 6-fold increase over plasma AUC at 4 and 24 h, respectively. The mean residence time of total platinum in the peritoneum was 4.7 h. Approximately 10% and 40% of plasma platinum was protein bound at 4 and 24 h after treatment, respectively, whereas peritoneal fluid platinum showed minimal protein binding. Peak plasma platinum levels were comparable to those recorded in previous studies with i.v. doses of carboplatin. Peritoneal clearance of carboplatin in these four patients appeared to be less than that previously reported for cisplatin. Further studies are in progress with higher doses of i.p. carboplatin.
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  • 3
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Leukemia cells isolated from eight patients with acute leukemia before treatment were examined for in vitro uptake of daunorubicin (DNR) and inhibition of DNA synthesis. In addition, plasma and cellular levels of DNR and daunorubicinol (DOL) were examined in six of the eight patients. Inhibition of DNA synthesis was determined with a 3H-thymidine incorporation assay. In vitro cellular 14C-DNR was quantified by means of liquid scintillation spectrometry, whereas in vivo DNR and DOL concentrations were determined by high-performance liquid chromatography. In vitro intracellular plateau concentrations of DNR were achieved within 1–2 h after continuous exposure to 0.01, 0.1, and 1.0 ug/ml in the majority of cases. Based on our in vitro studies, a dose-response curve was found between increasing intracellular DNR and incorporation of 3H-thymidine. Peak intracellular levels of DNR after treatment occurred immediately after administration of the drug, whereas intracellular DOL levels accumulated over several hours. Plasma concentrations of DNR and DOL were not useful in estimating target tissue concentrations or inhibition of 3H-thymidine incorporation. Extrapolation of in vivo cellular DNR concentrations to the in vitro dose-response curve allows an estimate of DNR sensitivity.
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  • 4
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Diethyldithiocarbamate (DDTC), a chelating agent that is a major metabolite of disulfuram, has been proposed as a potential rescue agent to reduce toxicity following high-dose cisplatin (HDCP) therapy. In the present study, we examined the pharmcologic interaction of HDCP and DDTC given as rescue therapy. Total plasma platinum and ultrafiltrate platinum pharmacokinetics and DDTC levels were determined in six patients with advanced malignancies who received a total of 11 cycles of HDCP with DDTC rescue. HDCP therapy (200 mg/m2 per cycle) consisted of 100 mg/m2 reconstituted in 250 cc 3% saline and infused over 3 h on days 1 and 8 of each 28-day cycle. DDTC rescue at a dose of 4 gm/m2 was given by an i.v. infusion (duration 1.5–3.5 h), beginning 45 min after the completion fo cisplatin infusion. Peak total and ultrafiltrate levels and cisplatin pharmacokinetics in this study were indistinguishable from those of previous studies using the same HDCP regimen without DDTC rescue. Ultrafiltrate or unbound plasma platinum was〈10% of total plasma platinum concentrations and demonstrated a biphasic pattern of elimination. Levels of DDTC predicted to be chemoprotective (〉400 μM) were achieved with the dose and schedule used in this study. These data demonstrate that DDTC can be targeted to protective plasma concentrations without significantly altering plasma cisplatin pharmacokinetics and support the potential usefulness of DDTC as a rescue agent following HDCP therapy.
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  • 5
    ISSN: 1432-069X
    Keywords: Key words Collagenase ; Matrix metalloproteinase ; Cutaneous ; Inflammation ; Phorbol esters
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteases which play key roles in extracellular matrix remodeling, connective tissue damage, inflammation and cell proliferation in a variety of tissues. Since MMP inhibitors have been recently shown to decrease proliferation of vascular smooth-muscle cells, and to prevent neutrophil infiltration in response to alkali burns, we sought to determine whether MMPs play a role in the pathogenesis of inflammatory or hyperproliferative skin disorders. The effects of a specific MMP inhibitor and its analogues on phorbol dibutyrate (PdiBu)-induced inflammation and epidermal hyperplasia in murine skin were assessed. Topical GM 6001, a hydroxamic acid analog with potent inhibitory activity against several MMPs, markedly inhibited PdiBu-induced increases in both ear thickness and ear punch-biopsy weight in a dose-dependent manner 30 h after topical application of PdiBu. Maximal inhibition (75%) was obtained at a dose of 100 μg/cm 2 ( P 〈 0.01). Moreover, histologic analysis revealed that GM 6001 decreased both the inflammatory cellular infiltrates and epidermal hyperplasia induced by PdiBu. Whereas similar results were found for GM 1489, an analog of GM 6001, acetohydroxamic acid, containing the critical metal ligand group but without the amino acid side chains necessary for binding to the MMPs, did not alter the response to PdiBu inflammation/hyperplasia. These results show that the MMP inhibitors, GM 6001 and GM 1489, are effective in reducing both the inflammatory and hyperproliferative responses that occur following topical phorbol ester application, suggesting a potential role for MMPs in cutaneous inflammatory dermatoses. Moreover, the delivery of this class of inhibitors across intact stratum corneum implies that MMP inhibition could provide an approach to the topical treatment of inflammatory dermatoses.
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  • 6
    ISSN: 1432-069X
    Keywords: Serine-palmitoyl transferase ; Sphingolipid synthesis ; Transepidermal water loss ; Barrier function ; Essential fatty acid deficiency ; Epidermal permeability barrier
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Sphingolipids, the predominant lipid species in mammalian stratum corneum play, a central role in permeability barrier homeostatis. Prior studies have shown that the epidermis synthesizes abundant sphingolipids, a process regulated by barrier requirements, and that inhibition of sphingolipid synthesis interferes with barrier homeostasis. To investigate further the relationship between epidermal sphingolipid metabolism and barrier function, we localized sphingolipid synthetic activity in murine epidermis under basal conditions, and following acute (acetone treatment) or chronic (essential fatty acid deficiency, EFAD) barrier perturbation, using dithiothreitol and/or the staphylococcal epidermolytic toxin to isolate the lower from the outer epidermis. Under basal conditions, both the activity of serine palmitoyl transferase (SPT), the rate-limiting enzyme of sphingolipid synthesis, and the rates of3H-H2O incorporation into sphingolipids were nearly equivalent in the lower and the outer epidermis. Following acute barrier perturbation, SPT activity increased significantly in both the lower (35%;P 〈 0.05) and the outer epidermal layers (60%;P 〈 0.01). The rates of3H-H2O incorporation into each major sphingolipid family, including ceramides, glucosylceramides and sphingomyelin, increased significantly in both the lower and the outer epidermis of treated flanks after acute barrier disruption. Finally, SPT activity was modestly elevated (20%;P 〈 0.01) in the lower but not in the outer epidermis of EFAD animals. These studies demonstrate the ability of both lower and outer epidermal cells to generate sphingolipids, and that permeability barrier homeostatic mechanisms appear to differentially regulate SPT acitivity and sphingolipid synthesis in the lower and the outer epidermis in response to acute and chronic barrier perturbation. Moreover, intraepidermal sites of sphingolipid synthesis displayed distinctive differences in the localization and alterations of cholesterologenesis in response to equivalent barrier perturbations.
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  • 7
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    ISSN: 0021-9614
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1600-0625
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The basis for the permeability barrier abnormality in lamellar ichthyosis (LI) is not known. LI is caused by mutations in the gene that encodes the enzyme, transglutaminase 1 (TGI), which is responsible for assembly of the cornified envelope (CE). TG1 also has been suggested recently to catalyze the covalent attachment of omega-hydroxyceramides (omega-OHCer) to the CE, forming the corneocyte-lipid envelope (CLE). We first assessed the barrier function and the permeability pathway of the water-soluble tracer, colloidal lanthanum, across the stratum corneum (SC) in patients with LI with absent (n = 4) or low (n = 2) TG1 activity/protein. Increased movement of tracer through the SC correlated with increased transcutaneous water loss, and tracer remained restricted to the SC interstices. Enhanced extracellular permeability, in turn, was explicable by truncation and fragmentation of extracellular lamellar membrane arrays. The resultant clefts in the SC interstices represent the likely pathway for increased water permeability. Moreover, tracer movement remained restricted to the interstices, despite the demonstration of increased corneocyte fragility associated with widespread variations in CE structure. Regardless of variability in CE structure, however, CLE structure and bound omega-OHCer content were normal. The normal CLE in LI may explain both the restriction of tracer to the SC interstices, as well as the presence of foreshortened membrane arrays with near-normal interlamellar dimensions. Finally, the demonstration of a normal CLE in LI also raises questions about the putative role of TG1 in forming the CLE. These results demonstrate: (1) the extracellular nature of increased permeability in LI; (2) discontinuities in extracellular membrane structures that account for the enhanced permeability in LI; (3) that these membrane abnormalities are both associated with and explained by abnormalities in the subjacent CE scaffold; and (4) an intact CLE is present in LI, despite abnormalities in the CE, which may restrict water movement to the SC interstices in LI.
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  • 9
    ISSN: 1520-6904
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    The @journal of organic chemistry 51 (1986), S. 5419-5421 
    ISSN: 1520-6904
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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