Impairment of Methotrexate Transport Is Common in Osteosarcoma Tumor Samples
Rebecca Sowers,
Bethanne D. Wenzel,
Condon Richardson,
Paul A. Meyers,
John H. Healey,
Adam S. Levy,
Richard Gorlick
Affiliations
Rebecca Sowers
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
Bethanne D. Wenzel
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center New York, NY 10065, USA
Condon Richardson
Charlotte Kimelman Cancer Institute, 9048 Sugar Estate, St. Thomas USVI 00802, British Virgin Islands
Paul A. Meyers
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center New York, NY 10065, USA
John H. Healey
Division of Orthopaedic Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center New York, NY 10065, USA
Adam S. Levy
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
Richard Gorlick
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
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.
