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  • 1
    Electronic Resource
    Electronic Resource
    Mechanisms of resistance to methotrexate in childhood acute lymphoblastic leukemia: circumvention of thymidylate synthase inhibition (1999)
    Springer
    Journal of cancer research and clinical oncology 125 (1999), S. 513-519 
    Details
    ISSN: 1432-1335
    Keywords: Key words Acute lymphoblastic leukemia ; Methotrexate polyglutamates ; Thymidylate synthase ; Salvage pathway ; Relapse
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: In about 25% of patients suffering from acute lymphoblastic leukemia (ALL) treatment failures occur that are most likely due to development of resistance to methotrexate (MTX). Blasts from patients with ALL were evaluated for MTX uptake, formation of long-chain MTX polyglutamates (MTX-Glu5+6), cytotoxicity and thymidylate synthase inhibition by MTX and compared to blasts from patients with acute myelogenous leukemia (AML). Methods: Radioactively labeled MTX-Glu n were analyzed by means of HPLC. Thymidylate synthase activity was measured by a tritium-release assay. Cytotoxicity was determined by trypan blue exclusion. Results: In most ALL blasts (n = 9) large amounts of MTX-Glu5+6 (1.06–7.03 pmol/107cells) and high cytotoxicity (43.5%–92.7%) were found, while in others small amounts of MTX-Glu5+6 (0.0–0.39 pmol/107cells) caused only weak cytotoxicity (6.0%–27.9%) (n = 5, 2 relapsed patients). Resistance to MTX in blasts from AML patients (n = 5) was also caused by reduced synthesis of MTX-Glu5+6 (0.0–0.42 pmol/107cells). In contrast, some ALL blasts (n = 7, 4 relapsed patients) were able to survive MTX treatment despite large amounts of MTX-Glu5+6 (1.5–5.05 pmol/107cells) and extensive thymidylate synthase inhibition. Conclusions: Since the majority of ALL patients were examined at first diagnosis, an inherent mechanism of resistance seems most likely. We propose a mechanism based on the switch of thymidylate synthesis to the salvage pathway.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004320050310
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  • 2
    Electronic Resource
    Electronic Resource
    Comparative analysis of methotrexate polyglutamates in lymphoblast preparations from bone marrow and blood, and the contribution of residual red blood cells (2000)
    Springer
    Journal of cancer research and clinical oncology 126 (2000), S. 407-411 
    Details
    ISSN: 1432-1335
    Keywords: Key words Acute lymphoblastic leukemia ; Methotrexate polyglutamates ; Lymphoblast preparation ; Red blood cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: Blasts isolated from bone marrow aspirates or blood samples of patients with acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) were compared for uptake of methotrexate (MTX) and formation of MTX polyglutamates (MTX-Glu n ). Red blood cells (RBC) from the same patient samples were also analyzed. Methods: Blasts were isolated by standard density centrifugation. RBC were prepared from the pellet of the same centrifugation. MTX-Glu n were analyzed by means of HPLC and radiochemical quantification. Results: In lymphoblasts isolated from blood, the distribution patterns of MTX-Glu n were the same as in bone marrow lymphoblasts, but the total amount of MTX-Glu n accumulated in blood lymphoblasts was reduced by 41%–51% when compared to the same number of bone marrow lymphoblasts of the same patient. RBC accumulated MTX but no formation of MTX-Glu n occurred. Conclusions: The determination of MTX and MTX-Glu n in lymphoblasts isolated from blood samples of patients with common ALL provides qualitative information on the capacity of the blasts to form MTX-Glu n since distribution patterns of MTX and MTX-Glu n parallel that of bone marrow lymphoblasts. The amounts of MTX-Glu n accumulated, however, were much lower in blood lymphoblasts. Blood lymphoblasts are therefore not useful for a quantitative analysis of MTX-Glu n . The contribution of RBC to MTX and MTX-Glu n in vitro is only marginal and residual RBC in lymphoblast preparations from bone marrow can therefore be ignored.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00008489
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  • 3
    Electronic Resource
    Electronic Resource
    Morbus Coats bei einem Jungen mit DiGeorge-Syndrom (1997)
    Springer
    Monatsschrift Kinderheilkunde 145 (1997), S. 1061-1065 
    Details
    ISSN: 1433-0474
    Keywords: Schlüsselwörter DiGeorge-Syndrom ; Morbus Coats ; Leukokorie ; Retinoblastom ; Amaurose im Kindesalter ; Key words DiGeorge-Syndrom ; Coats’ disease ; Leukocoria ; Retinoblastoma ; Amaurosis in childhood
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Coats’ disease is characterized by teleangiectatic and aneurysmal changes of the retinal vessels with secondary intra- and subretinal exudates. In most cases vision can be preserved by therapy at an early stage. In rare, advanced cases a total retinal detachment causes amaurosis. This case is the first description of Coats’ disease associated with DiGeorge-Syndrome. We report the case of an eight year old boy, who suffered from headache after ear surgery (tympanoplastic type I). Retinoblastoma could be exluded and Coats’ disease was diagnosed by ophthalmoscopy, computertomography and magnetic resonance imaging. Discussion: Until today the cause of Coats’ disease is unknown. The coincidence with DiGeorge-Syndrome seems to be accidental.
    Notes: Zusammenfassung Der Morbus Coats ist charakterisiert durch teleangiektatische und aneurysmatische Gefäßveränderungen der Retina und sekundäre intra- und subretinale Exsudate. Meist ist durch frühzeitige Therapie der Visus zu erhalten. In seltenen, fulminant verlaufenden Fällen können eine vollständige Amotio retinae und Erblindung auftreten. Dieser Fall ist die erste Beschreibung eines Morbus Coats bei einem DiGeorge-Syndrom. Wir berichten über einen 8jährigen Jungen mit einem DiGeorge-Syndrom, bei dem nach einer Tympanoplastik Typ I starke Kopfschmerzen auftraten. Durch Ophthalmoskopie, Computertomographie und Kernspintomographie konnten ein Retinoblastom ausgeschlossen und ein Morbus Coats diagnostiziert werden. Diskussion: Die Ursache des Morbus Coats ist bis heute nicht geklärt. Das Zusammentreffen mit dem DiGeorge-Syndrom ist wahrscheinlich zufällig.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001120050204
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    Paper (German National Licenses)
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