title: Circumvention of methotrexate resistance in childhood leukemia subtypes by rationally designed antifolates.
abstract: Cellular methotrexate (MTX) resistance may cause treatment failure in childhood common/preB-acute lymphoblastic leukemia (c/preB-ALL), T-lineage ALL (T-ALL), and acute myeloid leukemia (AML). The ex vivo potency of several antifolates (MTX, trimetrexate [TMQ], GW1843U89, multitargeted antifolate [MTA], Raltitrexed, and ZD9331) was studied via in situ inhibition of thymidylate synthase (TS). After short-term exposure, relapsed c/preB-ALL (rALL, n = 21), T-ALL (n = 22), and AML (n = 22) were 3-fold, 10-fold, and 6-fold less sensitive to MTX (P </=.01) compared with initial c/preB-ALL (n = 43). This difference in resistance was not observed for TMQ. Also for GW1843U89 and MTA, no resistance was observed in rALL and AML compared with c/preB-ALL. T-ALL compared with c/preB-ALL tended to be less resistant to GW1843U89 (3-fold) and MTA (6-fold) than to MTX (10-fold) (P =.06). Raltitrexed was more active against c/preB-ALL compared with the other subtypes. After 21 hours continuous incubation, T-ALL and AML samples were equally sensitive as c/preB-ALL to MTX, but rALL was 3-fold resistant to MTX compared with initial c/preB-ALL (P =.003). The resistance of rALL was circumvented by TMQ (1-fold; P =.03) and GW1843U89 (1.4-fold; P =. 004). Novel antifolates, except MTA, displayed a more potent TS inhibition than MTX during continuous exposure. These results suggest that MTX resistance in AML and T-ALL can be circumvented by continuous exposure, and that novel antifolates should be explored further for MTX-resistant T-ALL, rALL, and AML cells.
authors.affiliation: Department of Pediatric Hematology/Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands. marianne.rots@azvu.nl
authors.forename: M G
authors.initials: MG
authors.lastname: Rots
authors.forename: R
authors.initials: R
authors.lastname: Pieters
authors.forename: G J
authors.initials: GJ
authors.lastname: Peters
authors.forename: C H
authors.initials: CH
authors.lastname: van Zantwijk
authors.forename: R
authors.initials: R
authors.lastname: Mauritz
authors.forename: P
authors.initials: P
authors.lastname: Noordhuis
authors.forename: J C
authors.initials: JC
authors.lastname: Willey
authors.forename: K
authors.initials: K
authors.lastname: Hählen
authors.forename: U
authors.initials: U
authors.lastname: Creutzig
authors.forename: G
authors.initials: G
authors.lastname: Janka-Schaub
authors.forename: G J
authors.initials: GJ
authors.lastname: Kaspers
authors.forename: A J
authors.initials: AJ
authors.lastname: Veerman
authors.forename: G
authors.initials: G
authors.lastname: Jansen
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm; D005493:Folic Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D008727:Methotrexate / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D016597:Trimetrexate / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D011799:Quinazolines; D013876:Thiophenes; C094299:ZD 9331; C068874:raltitrexed; D016597:Trimetrexate; D008727:Methotrexate