Entwicklung eines Antikörper- Assays zur Risikoabschätzung anaphylaktischer Reaktionen sowie der Inaktivierungswahrscheinlichkeit des Enzyms L- Asparaginase in der Therapie der akuten lymphatischen Leukämie

L-Asparaginase ist ein bakterielles Enzym, das seit über 30 Jahren im Rahmen einer Polychemotherapie zur Behandlung akuter lympha-tischer Leukämien und einiger maligner Lymphome eingesetzt wird. Asparaginase katalysiert die Hydrolyse von L-Asparagin und bewirkt auf diese Weise eine Depletion des Asp...

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Bibliographic Details
Main Author: Randow, Josefine von
Contributors: Röhm, Karl-Heinz, Prof. Dr. (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2005
Online Access:PDF Full Text
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L-asparaginase is a bacterial enzyme that has been used for over thirty years for polychemotherapy of acute lymphatic leukaemia and some malignant lymphomas. Asparaginase catalyzes the hydrolysis of L-asparaginase, which leads to depletion of asparagine in blood plasma. Since this amino acid is essential for tumor growth, the low concentration of asparagine consequently suppresses the replication of malignant cells. Major complications during therapy with asparaginase are hypersensitivity reactions and a so-called silent inactivation of the enzyme. Prediction of a potential hypersensitivity reaction or a silent inactivation would lead to a significant improvement in therapy with asparaginase. The immunological test that has been used to detect serum antibodies that might be responsible for hypersensitivity reactions or silent inactivation shows poor sensitivity and specificity. This test is therefore not helpful for predicting complications of aspariginase therapy. Based on the hypothesis that the antibodies are epitope specific, asparaginase-DNA was digested without knowledge of the precise location of the epitopes to obtain five asparaginase fragments with a known amino acid sequence. The use of these fragments as antigens allowed identification of an early antibody population against the c-terminal fragment (237-326) in patients with silent inactivation. A correlation between antibody titer against one of the other fragments and silent inactivation could not be found. These results establish a promising basis for further development of this assay. By performing distinct epitope mapping, the fragments used for immunological tests will be more selective in the future. Further tests in patients receiving aspariginase therapy will be necessary to statistically verify the predictive value of this new approach.