Methotrexate pharmacology and resistance in childhood acute lymphoblastic leukemia.
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.
Matherly
L H
LH
Karmanos Cancer Institute, Department of Pharmacology, Wayne State University, Detroit, Michigan, USA.
Taub
J W
JW
D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001692:Biological Transport; D001711:Biotransformation; D002352:Carrier Proteins / Q000378:metabolism; D002648:Child; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D004198:Disease Susceptibility; D018572:Disease-Free Survival; D004314:Down Syndrome / Q000150:complications; D019008:Drug Resistance, Neoplasm; D005493:Folic Acid Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D008727:Methotrexate / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011099:Polyglutamic Acid / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D011379:Prognosis; D058978:Reduced Folate Carrier Protein; D012074:Remission Induction; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D002352:Carrier Proteins; D005493:Folic Acid Antagonists; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; C120043:SLC19A2 protein, human; D011099:Polyglutamic Acid; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate