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Sarcoma
Volume 2011, Article ID 834170, 5 pages
http://dx.doi.org/10.1155/2011/834170
Research Article

Impairment of Methotrexate Transport Is Common in Osteosarcoma Tumor Samples

1Division 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
2Department of Pediatrics, Memorial Sloan-Kettering Cancer Center New York, NY 10065, USA
3c/o Veterans Administration New York Harbor Healthcare System, Narrows Institute for Biomedical Research Brooklyn, NY 11209, USA
4Charlotte Kimelman Cancer Institute, 9048 Sugar Estate, St. Thomas USVI 00802, British Virgin Islands
5Division of Orthopaedic Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center New York, NY 10065, USA

Received 13 September 2010; Accepted 15 November 2010

Academic Editor: Stephen Lessnick

Copyright © 2011 Rebecca Sowers et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.