Circumvention of Methotrexate Resistance in Childhood Leukemia Subtypes by Rationally Designed Antifolates (2024)

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Ex vivo activity of methotrexate versus novel antifolate inhibitors of dihydrofolate reductase and thymidylate synthase against childhood leukemia cells

Marcel Bekkenk

Clinical Cancer Research

Leukemic cells of 27 children [14 patients with initial acute lymphoblastic leukemia (iALL), 8 patients with relapsed ALL (rALL), and 5 patients with acute nonlymphoblastic leukemia (ANLL)] were evaluated for their sensitivity to methotrexate (MTX) and five novel antifolate drugs, which have the potential to circumvent MTX resistance. The novel antifolates include a polyglutamatable [edatrexate (EDX)] and a lipophilic (trimetrexate) inhibitor of dihydrofolate reductase and two polyglutamatable inhibitors (ZD1694 and GW1843U89) and one lipophilic inhibitor (AG337) of thymidylate synthase (TS). Drug activity was assessed via the determination of in situ inhibition of TS activity after exposing leukemic cells to antifolate drugs for: (a) 3 h, followed by a 15-h drug-free period; and (b) 18 h of continuous exposure. For human CEM leukemia cell lines with well-defined mechanisms of resistance to MTX, in situ TS inhibition correlated with the growth-inhibitory effects of MTX and the novel...

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Disparate mechanisms of antifolate resistance provoked by methotrexate and its metabolite 7-hydroxymethotrexate in leukemia cells: implications for efficacy of methotrexate therapy

Alan Fotoohi

Blood, 2004

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Pharmacokinetics of high-dose methotrexate in infants treated for acute lymphoblastic leukemia

Pediatric Blood & Cancer, 2009

BackgroundInterfant-99 was an international collaborative treatment protocol for infants with acute lymphoblastic leukemia (ALL).Interfant-99 was an international collaborative treatment protocol for infants with acute lymphoblastic leukemia (ALL).ProcedureWe collected data on 103 infants at the time of their first treatment with high-dose methotrexate (HD MTX), 5 g/m2. Children <6 months of age received two-third of the calculated dose based on body surface area (BSA), children 6–12 months three-fourth of the calculated dose, and children >12 months full dose.We collected data on 103 infants at the time of their first treatment with high-dose methotrexate (HD MTX), 5 g/m2. Children <6 months of age received two-third of the calculated dose based on body surface area (BSA), children 6–12 months three-fourth of the calculated dose, and children >12 months full dose.ResultsThe median steady-state MTX concentration at the end of the 24-hr infusion was 57.8 µM (range 9.5–313). The median systemic clearance was 6.22 L/hr/m2 BSA, and tended to increase with age (P = 0.099). Boys had higher clearance than girls, 6.77 and 5.28 L/hr/m2 (P = 0.030), and tended to have lower median MTX concentration at 24 hr. Eight infants had MTX levels below 20 µM, a level judged to be sufficient in B-lineage ALL in children >1 year of age. All infants tolerated the dose well enough to receive a second dose of HD MTX without dose reduction. We found no significant effect on disease-free survival for MTX steady-state concentration, MTX clearance, or time to MTX below 0.2 µM.The median steady-state MTX concentration at the end of the 24-hr infusion was 57.8 µM (range 9.5–313). The median systemic clearance was 6.22 L/hr/m2 BSA, and tended to increase with age (P = 0.099). Boys had higher clearance than girls, 6.77 and 5.28 L/hr/m2 (P = 0.030), and tended to have lower median MTX concentration at 24 hr. Eight infants had MTX levels below 20 µM, a level judged to be sufficient in B-lineage ALL in children >1 year of age. All infants tolerated the dose well enough to receive a second dose of HD MTX without dose reduction. We found no significant effect on disease-free survival for MTX steady-state concentration, MTX clearance, or time to MTX below 0.2 µM.ConclusionsOur data provide no support for a change in the dosing rules for MTX used in Interfant-99. However, in view of the poor treatment results for infants, one might consider increase in the dose for patients who reach plasma levels below median after the first MTX dose. Pediatr Blood Cancer 2009;52:596–601. © 2009 Wiley-Liss, Inc.Our data provide no support for a change in the dosing rules for MTX used in Interfant-99. However, in view of the poor treatment results for infants, one might consider increase in the dose for patients who reach plasma levels below median after the first MTX dose. Pediatr Blood Cancer 2009;52:596–601. © 2009 Wiley-Liss, Inc.

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Impaired methotrexate polyglutamylation in a human leukemia cell line resistant to short-term, high-dose methotrexate

Joseph Bertino

Pharmacological research communications, 1988

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Effects of High Dose Methotrexate and Delayed Elimination on Myelotoxicity Progression in Children with Acute Lymphoblastic Leukemia

Usama El Safy

Afro-Egyptian Journal of Infectious and Endemic Diseases, 2017

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Basis for natural resistance to methotrexate in human acute non-lymphocytic leukemia

Peter Steinherz

Leukemia Research, 1991

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Development of an assay system for the detection and classification of methotrexate resistance in fresh human leukemic cells

Joseph Bertino

Cancer research, 1986

An assay system was developed for the detection and classification of methotrexate resistance in fresh human leukemic cells. Mechanisms of resistance to be identified were: overexpression of dihydrofolate reductase, decreased cellular uptake of methotrexate, decreased affinity of dihydrofolate reductase for methotrexate, decreased polyglutamylation of methotrexate, and low thymidylate synthase activity. The initial screening procedure utilizes 3H release after addition of [5-3H]-2&#39;-deoxyuridine as a measure of intracellular activity of thymidylate synthase and of DNA synthesis; 3H release is assayed after 3-h incubations with methotrexate, trimetrexate, or gamma-fluoromethotrexate and after 4-h incubations with these agents followed by a 6-h incubation in drug free medium. The pattern of DNA synthesis inhibition and recovery under these two sets of conditions establishes the presence or absence of methotrexate resistance and allows a tentative classification of the resistance me...

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Elevated dihydrofolate reductase and impaired methotrexate transport as elements in methotrexate resistance in childhood acute lymphoblastic leukemia

Jeffrey Taub

Blood, 1995

A retrospective study of clinical resistance to methotrexate (MTX) was performed on 29 archival specimens of frozen lymphoblasts obtained from children with acute lymphoblastic leukemia (ALL), including 19 at initial presentation and 10 at first relapse. Blasts were assayed for dihydrofolate reductase and MTX transport by flow cytometry using the fluorescent methotrexate analog, PT430 (Rosowsky et al, J Biol Chem 257:14162, 1982). In contrast to tissue culture cells, patient blasts were often heterogeneous for dihydrofolate reductase content. Of the 19 specimens at initial diagnosis, 7 exhibited dual blast populations, characterized by threefold to 10-fold differences in relative dihydrofolate reductase; the dihydrofolate reductase-overproducing populations comprised 12% to 68% of the total blasts for these specimens. Remission duration intervals for patients exhibiting dual blast populations were notably shorter than for patients expressing a single blast population with lower dihy...

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An assay for the determination of reduced methotrexate accumulation in cells displaying limited viability in vitro

Murray Norris

Cancer Letters, 1995

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Assessment of traditional anomalies associated with folate antagonist methotrexate in chick embryo

Dr. Rida Amjad

Pure and Applied Biology, 2020

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Circumvention of Methotrexate Resistance in Childhood Leukemia Subtypes by Rationally Designed Antifolates (2024)

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