Cytotoxicity of methotrexate and trimetrexate and its reversal by folinic acid in human leukemic CCRF-CEM cells with carrier-mediated and receptor-mediated folate uptake.
The cytotoxic effects of the antifolates methotrexate (MTX) and trimetrexate (TMQ) were investigated for two human leukemic CCRF-CEM cell lines, one expressing the "classical" reduced folate/MTX carrier (CEM-RF), another lacking this carrier but expressing a membrane associated folate binding protein (CEM-FBP). CEM-FBP cells were found to be highly resistant to MTX compared to CEM-RF cells, especially in short exposures. For example, after 4 h incubation, IC50 values for MTX were 251 microM and 0.98 microM for CEM-FBP and CEM-RF cells, respectively. On the other hand, CEM-FBP cells were much more sensitive to the lipophilic antifolate TMQ than CEM-RF cells as shown by IC50 values (after 4 h of exposure) of 0.059 microM and 7.5 microM, respectively. Finally, the reversal of TMQ cytotoxicity by folinic acid was significantly impaired for CEM-FBP cells, in contrast to CEM-RF cells. These results indicate that the nature of the membrane transport system for folates can be a critical determinant in tumor cell sensitivity or resistance to antifolates.
van der Veer
L J
LJ
Department of Internal Medicine, University Hospital Utrecht, The Netherlands.
Westerhof
G R
GR
Rijksen
G
G
Schornagel
J H
JH
Jansen
G
G
D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D002955:Leucovorin / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D008727:Methotrexate / Q000378:metabolism / Q000633:toxicity*; D011799:Quinazolines / Q000378:metabolism / Q000633:toxicity*; D011956:Receptors, Cell Surface; D016597:Trimetrexate; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D011799:Quinazolines; D011956:Receptors, Cell Surface; D005492:Folic Acid; D002955:Leucovorin; D016597:Trimetrexate; D008727:Methotrexate