Development of methotrexate resistance in a human squamous cell carcinoma of the head and neck in culture.
Four methotrexate (MTX)-resistant sublines of a human squamous cell carcinoma (SCC15) were established in culture by progressive dose escalation. The biochemical basis of resistance was studied. The line with the lowest resistance (R1) had a normal dihydrofolate reductase (DHFR) content but showed decreased MTX transport and polyglutamation. Lines of intermediate resistance (R2 and R3) showed an increased DHFR content and DHFR gene copy number and a defect in MTX transport. The line with the greatest resistance (R4) showed increased DHFR content and gene copy number but nearly normal MTX transport. These results demonstrate that multiple mechanisms of MTX resistance occur in human epithelial cells in culture. We also find evidence of alterations in DHFR gene expression. The MTX-resistant cells were either not cross-resistant or only partly cross-resistant to two lipophilic MTX ester derivatives. These compounds are of potential therapeutic interest for the treatment of MTX-resistant tumors.
D001692:Biological Transport; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005784:Gene Amplification; D005786:Gene Expression Regulation; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000378:metabolism; D011099:Polyglutamic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D014062:Tongue Neoplasms / Q000188:drug therapy*
D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate