A comparison of the effects of antitumor agents upon normal human epidermal keratinocytes and human squamous cell...

The pharmacologic responses of normal and malignant epidermal cells to chemotherapeutic agents were examined in a system which consists of a serum-free "defined" medium. The effects of methotrexate (MTX), fluorodeoxyuridine (FUDR), and hydroxyurea upon cell growth, DNA synthesis, thymidylate synthase activity, and dihydrofolate reductase (DHFR) activity were compared in normal human epidermal keratinocytes (NHEK), newborn epidermal cells (NEC), human squamous cell carcinoma (SCC-25), and a methotrexate-resistant human squamous cell carcinoma (SCC-15R). Normal keratinocytes were found to be 10(3) to 10(4) times less sensitive to the effects of MTX and FUDR than the malignant cells with respect to growth and DNA synthesis. The differential sensitivity to MTX and FUDR was not due to differences in growth media, increased target enzyme activity, e.g., DHFR and thymidylate synthase, or impaired transport of these drugs. The results indicate that the mechanism for the increased sensitivity of the squamous cell carcinoma to MTX and FUDR must involve a process which is distal to the de novo synthesis of dTMP.