Biomedical subjects

Inge M Appel

Publications and source records attributed to Inge M Appel.

4 recordsLinked to original sources

PubMed2006

Up-regulation of asparagine synthetase expression is not linked to the clinical response L-asparaginase in pediatric acute lymphoblastic leukemia.

L-asparaginase (L-Asp) is an effective drug for treatment of children with acute lymphoblastic leukemia (ALL). The effectiveness is generally thought to result from a rapid depletion of asparagine in serum and cells. Asparagine synthetase (AS) opposes the action of L-Asp by resynthesis of asparagine. In vitro, resistance to L-Asp has been associated with up-regulation of AS mRNA expression. We monitored AS mRNA levels in leukemic cells before and during 5 days after intravenous administration of 1000 IU/m(2) pegylated L-asparaginase (PEG-Asp) in a therapeutic window in children with ALL at initial diagnosis. Within 24 hours, AS mRNA levels increased by 3.5-fold and remained stable in the following 4 days. Baseline and L-Asp-induced expression levels of AS did not differ between clinically good, intermediate, and poor responders to PEG-Asp. No significant difference of AS mRNA up-regulation was found between precursor B- and T-ALL or between hyperdiploids, TEL/AML1 rearranged ALL or absence of genetic abnormalities. In 3 of 12 patients with T-ALL even a slight down-regulation of AS mRNA expression upon L-Asp exposure was found. In conclusion, although L-Asp exposure induces the expression of AS mRNA, the up-regulated gene expression does not correlate with an early clinical poor response to this drug in children with ALL.

Adolescent↗

PubMed2006

Changes in hypercoagulability by asparaginase: a randomized study between two asparaginases.

Alterations in hemostasis have frequently been observed in children with acute lymphoblastic leukemia. Thrombotic events are well documented in patients receiving L-asparaginase as a single agent or in combination with other chemotherapeutic drugs. The present prospective, randomized study evaluated the effect of two different L-asparaginase preparations, native Escherichia coli L-asparaginase (Crasnitin; Bayer AG, Leverkusen, Germany; n = 10) and L-asparaginase derived from Erwinia chrysanthemi (Erwinase; Porton Pruducts, London, UK; n = 10) on the changes in parameters concerning hypercoagulability. Patients were randomized to receive a total of eight doses of 10,000 IU/m2 L-asparaginase intravenously with intervals of 3 days during induction therapy. Before starting L-asparaginase treatment all patients had already demonstrated an increased thrombin generation shown by the elevated levels of prothrombin fragment 1+2 and thrombin antithrombin III, presumably due to therapy with prednisone, daunorubicin and vincristine. A significant decrease in alpha2-antiplasmin and plasminogen levels was measured in the E. coli L-asparaginase but not in Erwinase-treated patients. Increased thrombin generation combined with a decrease in alpha2-antiplasmin and plasminogen levels may lead to a state of increased risk for thrombosis due to a delay in fibrin elimination in E. coli L-asparaginase-treated patients only.

Adolescent↗

PubMed2005

Asparagine synthetase expression is linked with L-asparaginase resistance in TEL-AML1-negative but not TEL-AML1-positive pediatric acute lymphoblastic leukemia.

Resistance to L-asparaginase in leukemic cells may be caused by an elevated cellular expression of asparagine synthetase (AS). Previously, we reported that high AS expression did not correlate to L-asparaginase resistance in TEL-AML1-positive B-lineage acute lymphoblastic leukemia (ALL). In the present study we confirmed this finding in TEL-AML1-positive patients (n = 28) using microarrays. In contrast, 35 L-asparaginase-resistant TEL-AML1-negative B-lineage ALL patients had a significant 3.5-fold higher AS expression than 43 sensitive patients (P < .001). Using real-time quantitative polymerase chain reaction (RTQ-PCR), this finding was confirmed in an independent group of 39 TEL-AML1-negative B-lineage ALL patients (P = .03). High expression of AS was associated with poor prognosis (4-year probability of disease-free survival [pDFS] 58% +/- 11%) compared with low expression (4-year pDFS 83% +/- 7%; P = .009). We conclude that resistance to l-asparaginase and relapse risk are associated with high expression of AS in TEL-AML1-negative but not TEL-AML1-positive B-lineage ALL.

Asparaginase↗

PubMedDate not supplied

Supratentorial arterial ischemic stroke following cerebellar tumor resection in two children.

We describe two children who developed ischemic strokes in the territory of the middle cerebral artery, one 7 days and one 11 days after resection of a cerebellar tumor. In the first child, another infarction occurred in the territory of the contralateral middle cerebral artery 5 days after the first stroke. No specific cause or underlying risk factor other than the surgical procedure was found. The subacute clinical course at stroke onset resembled that of the 'posterior fossa syndrome', suggesting a common underlying mechanism.

Cerebellar Neoplasms↗