title: Impairment of methotrexate transport is common in osteosarcoma tumor samples.
abstract: Osteosarcoma does not respond well to conventional dose methotrexate but does respond to high-dose methotrexate. Previous work has indicated that this resistance may be due to impaired transport of methotrexate across the cell membrane. In this study, the PT430 competitive displacement assay was adapted to evaluate methotrexate transport in 69 high-grade osteosarcoma tumor samples. All samples studied were shown to have relatively impaired methotrexate transport by PT430 assay. Ninety-nine percent of the samples had less than 20% PT430 displacement by methotrexate. Eighty-eight percent exhibited displacement by methotrexate at less than 50% of the displacement by trimetrexate. The high frequency of impaired transport suggests the presence of decreased functionality of the reduced folate carrier protein. The overwhelming presence of impaired transport may explain why methotrexate needs to be given in high doses to be effective in osteosarcoma therapy and suggests that reduced folate carrier-independent antifolates should be explored.
authors.affiliation: Division of Hematology/Oncology, Department of Pediatrics, The Children's Hospital at Montefiore, The Albert Einstein College of Medicine of Yeshiva University, 3415 Bainbridge Avenue, Rosenthal Rm 300, Bronx, NY 10467, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sowers
authors.forename: Bethanne D
authors.initials: BD
authors.lastname: Wenzel
authors.forename: Condon
authors.initials: C
authors.lastname: Richardson
authors.forename: Paul A
authors.initials: PA
authors.lastname: Meyers
authors.forename: John H
authors.initials: JH
authors.lastname: Healey
authors.forename: Adam S
authors.initials: AS
authors.lastname: Levy
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick