Impairment of Methotrexate Transport Is Common in Osteosarcoma Tumor Samples
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 a...
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2011-01-01
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Series: | Sarcoma |
Online Access: | http://dx.doi.org/10.1155/2011/834170 |
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doaj-592652e32f9248529223e0e0332ac6112020-11-24T23:17:48ZengHindawi LimitedSarcoma1357-714X1369-16432011-01-01201110.1155/2011/834170834170Impairment of Methotrexate Transport Is Common in Osteosarcoma Tumor SamplesRebecca Sowers0Bethanne D. Wenzel1Condon Richardson2Paul A. Meyers3John H. Healey4Adam S. Levy5Richard Gorlick6Division 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, USADepartment of Pediatrics, Memorial Sloan-Kettering Cancer Center New York, NY 10065, USACharlotte Kimelman Cancer Institute, 9048 Sugar Estate, St. Thomas USVI 00802, British Virgin IslandsDepartment of Pediatrics, Memorial Sloan-Kettering Cancer Center New York, NY 10065, USADivision of Orthopaedic Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center New York, NY 10065, USADivision 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, USADivision 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, USAOsteosarcoma 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.http://dx.doi.org/10.1155/2011/834170 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rebecca Sowers Bethanne D. Wenzel Condon Richardson Paul A. Meyers John H. Healey Adam S. Levy Richard Gorlick |
spellingShingle |
Rebecca Sowers Bethanne D. Wenzel Condon Richardson Paul A. Meyers John H. Healey Adam S. Levy Richard Gorlick Impairment of Methotrexate Transport Is Common in Osteosarcoma Tumor Samples Sarcoma |
author_facet |
Rebecca Sowers Bethanne D. Wenzel Condon Richardson Paul A. Meyers John H. Healey Adam S. Levy Richard Gorlick |
author_sort |
Rebecca Sowers |
title |
Impairment of Methotrexate Transport Is Common in Osteosarcoma Tumor Samples |
title_short |
Impairment of Methotrexate Transport Is Common in Osteosarcoma Tumor Samples |
title_full |
Impairment of Methotrexate Transport Is Common in Osteosarcoma Tumor Samples |
title_fullStr |
Impairment of Methotrexate Transport Is Common in Osteosarcoma Tumor Samples |
title_full_unstemmed |
Impairment of Methotrexate Transport Is Common in Osteosarcoma Tumor Samples |
title_sort |
impairment of methotrexate transport is common in osteosarcoma tumor samples |
publisher |
Hindawi Limited |
series |
Sarcoma |
issn |
1357-714X 1369-1643 |
publishDate |
2011-01-01 |
description |
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. |
url |
http://dx.doi.org/10.1155/2011/834170 |
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