title: The mechanism of differential sensitivity to methotrexate of normal and malignant human epidermal cells.
abstract: Squamous carcinoma cells are much more sensitive (greater than 10(4) times) to the cytotoxic effects of methotrexate (MTX) and 5-fluorodeoxyuridine (FUDR) than are normal human keratinocytes as measured by cell growth. Among the drugs tested, this phenomenon was found to be specific for MTX and FUDR, since arabinosylcytidine (ARA-C), 13-bis-chloroethylnitrosourea (BCNU), and daunomycin failed to show differences in inhibition between the normal and malignant cell lines. Drug uptake studies did not reveal a significant difference in MTX intracellular levels between malignant and normal epidermal cell lines at 60 min. Thymidine (TdR) salvage was assessed by examining the effects of the presence of 3 microM TdR on MTX-induced cytotoxicity. On the withdrawal of TdR, normal cells demonstrated an increased level of inhibition amounting to 4 orders of magnitude, whereas the squamous-cell carcinoma cells showed no change in sensitivity. Interestingly, the immortal nontumorigenic keratinocyte line (NM-110) was similarly not rescued by the addition of TdR. The high degree of sensitivity TO MTX shown by squamous-cell carcinoma (SCC) and NM-110 cells is attributable to a significant diminution of their ability to use exogenous TdR as compared with that of normal keratinocytes and might be indicative of a biochemical change associated with cellular immortality.
authors.affiliation: Laboratory of Molecular Dermatologic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
authors.forename: M M
authors.initials: MM
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Ratliff
authors.forename: G B
authors.initials: GB
authors.lastname: FitzGerald
authors.forename: M M
authors.initials: MM
authors.lastname: Wick
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
chemical_list: D008727:Methotrexate