Intrinsic resistance to methotrexate in human soft tissue sarcoma cell lines.
A human fibrosarcoma cell line, HT-1080, and four new cell lines (HS-16, HS-28, HS-30, and HS-42) were established from untreated patients with mesenchymal chondrosarcoma, peripheral nerve sheath sarcoma, malignant hemangiopericytoma, and mixed mesodermal tumor, respectively, and were used for analysis of mechanisms of intrinsic resistance to methotrexate. All four new cell lines were resistant to methotrexate as determined by inhibition of thymidylate synthase in whole cells and by growth inhibition, as compared with HT-1080, a methotrexate sensitive cell line. Methotrexate uptake, level of dihydrofolate reductase, and inhibition of this enzyme by methotrexate in the four cell lines were comparable to HT-1080 cells. However, levels of long chain polyglutamates (glu3-5) of methotrexate achieved after a 24-h incubation with this drug were much lower in the four new cell lines as compared to the HT-1080 cell line (5- to 20-fold lower). The low levels of methotrexate polyglutamates formed is likely the major cause of intrinsic methotrexate resistance in these new sarcoma cell lines.
Li
W W
WW
Laboratory of Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Lin
J T
JT
Schweitzer
B I
BI
Tong
W P
WP
Niedzwiecki
D
D
Bertino
J R
JR
D004351:Drug Resistance; D006801:Humans; D008727:Methotrexate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D010453:Peptide Synthases / Q000378:metabolism; D011099:Polyglutamic Acid / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D016597:Trimetrexate / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C036539:fluoresceinated methotrexate; D011099:Polyglutamic Acid; D013762:Tetrahydrofolate Dehydrogenase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; D016597:Trimetrexate; D008727:Methotrexate