Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A human fibrosarcoma cell line, HT-1080, and four new cell lines (HS-16, HS-28, HS-30, and HS-42) were established from untreated patients with mesenchymal chondrosarcoma, peripheral nerve sheath sarcoma, malignant hemangiopericytoma, and mixed mesodermal tumor, respectively, and were used for analysis of mechanisms of intrinsic resistance to methotrexate. All four new cell lines were resistant to methotrexate as determined by inhibition of thymidylate synthase in whole cells and by growth inhibition, as compared with HT-1080, a methotrexate sensitive cell line. Methotrexate uptake, level of dihydrofolate reductase, and inhibition of this enzyme by methotrexate in the four cell lines were comparable to HT-1080 cells. However, levels of long chain polyglutamates (glu3-5) of methotrexate achieved after a 24-h incubation with this drug were much lower in the four new cell lines as compared to the HT-1080 cell line (5- to 20-fold lower). The low levels of methotrexate polyglutamates formed is likely the major cause of intrinsic methotrexate resistance in these new sarcoma cell lines.
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PMID:Intrinsic resistance to methotrexate in human soft tissue sarcoma cell lines. 137 1

Impressive gains have been made in the therapy of childhood acute lymphoblastic leukemia (ALL) in recent years such that remissions today are commonly achieved in up to 95% of patients and long term disease-free survival rates approach 70%. Methotrexate is a key component in ALL consolidation and maintenance therapies and is administered intrathecally in the prophylaxis and treatment of central nervous system leukemia. Critical determinants of methotrexate sensitivity and resistance (dihydrofolate reductase levels, methotrexate membrane transport, methotrexate polyglutamylation) previously described in cultured cells have recently been identified in lymphoblasts from children with ALL. Heterogenous expressions of increased dihydrofolate reductase or impaired methotrexate transport can be detected in both diagnostic and relapsed ALL specimens by flow cytometry with fluorescent methotrexate analogues. Lymphoblasts from children with ALL synthesize long chain polyglutamates and correlations have been established between the accumulation of methotrexate polyglutamates in ALL blasts and characteristic patient prognostic features. Variations in methotrexate polyglutamate accumulation may reflect changes in polyglutamate synthetic or degradative enzymes, or may be secondary to changes in methotrexate influx or dihydrofolate reductase levels. Other critical elements in treatment response to methotrexate include the dose and route of methotrexate administration, its catabolism to 7-hydroxymethotrexate, and the rate of methotrexate plasma clearance. A unique relationship exists between chromosome 21 and ALL leukemogenesis, and response to treatment including methotrexate. A better understanding of the molecular bases of methotrexate response and the development of methotrexate resistance in childhood ALL should facilitate further improvements in the effectiveness of methotrexate-based chemotherapy for this disease.
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PMID:Methotrexate pharmacology and resistance in childhood acute lymphoblastic leukemia. 917