Sowers Rebecca, Wenzel Bethanne D, Richardson Condon, Meyers Paul A, Healey John H, Levy Adam S, Gorlick Richard
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.
Sarcoma. 2011;2011:834170. doi: 10.1155/2011/834170. Epub 2010 Dec 22.
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.
骨肉瘤对常规剂量的甲氨蝶呤反应不佳，但对高剂量甲氨蝶呤有反应。先前的研究表明，这种耐药性可能是由于甲氨蝶呤跨细胞膜转运受损所致。在本研究中，采用PT430竞争性置换试验来评估69例高级别骨肉瘤肿瘤样本中甲氨蝶呤的转运情况。通过PT430试验，所有研究样本均显示甲氨蝶呤转运相对受损。99%的样本中甲氨蝶呤对PT430的置换率低于20%。88%的样本中甲氨蝶呤的置换率低于三甲曲沙置换率的50%。转运受损的高频率表明还原型叶酸载体蛋白的功能降低。转运受损的普遍存在可能解释了为什么在骨肉瘤治疗中需要给予高剂量的甲氨蝶呤才能有效，并表明应探索不依赖还原型叶酸载体的抗叶酸药物。
