Open AccessDevelopment of methotrexate resistance in a human squamous cell carcinoma of the head and neck in culture.
Author(s) -
rd E Frei,
A. Rosowsky,
Joel E. Wright,
Carol A. Cucchi,
Judith A. Lippke,
Thomas J. Ervin,
Jacques Jolivet,
William A. Haseltine
Publication year - 1984
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.81.9.2873
Subject(s) - dihydrofolate reductase , methotrexate , cell culture , gene , cancer research , biology , epidermoid carcinoma , drug resistance , squamous carcinoma , cell , carcinoma , microbiology and biotechnology , chemistry , biochemistry , immunology , genetics
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.