AUGMENTATION OF 1-BETA-D-ARABINOFURANOSYLCYTOSINE RESISTANCE IN HUMAN KB EPIDERMOID CARCINOMA-CELLS UPON INDUCTION OF A 2ND RESISTANCE TO VINCRISTINE

Abstract

Human KB epidermoid carcinoma cells (KB/p) and their variant cells (KB/ara-C) resistant to 1-.beta.-D-arabinofuranosylcytosine (ara-C) that were not cross-resistant to vincristine (VCR) were exposed to increasing concentrations of VCR to establish VCR resistant cells (KB/VCR) and doubly resistant variant cells (KB/ara-C/VCR). KB/VCR and KB/ara-C/VCR cells showed a similar increase in resistance to VCR (about 337- to 660-fold) over that of the parent KB/p cells. KB/ara-C showed a 911-fold increase in resistance to ara-C, while KB/ara-C/VCR showed a 60,837-fold increase in resistance to ara-C compared with the parent cells. The concentration of ara-C required for 50% inhibition of KB/ara-C/VCR cells was much higher (67-fold) than that for KB/ara-C cells, although the concentration of ara-C required for 50% inhibition of KB/VCR cells was 12-fold that for KB/p cells. Thus the acquisition of resistance to a second drug by these human KB cells augmented their resistance to the first drug. Induction of resistance of to ara-C or VCR resulted in marked decrease in cellular uptake of the respective drugs, but there was no difference in cellular uptakes of ara-C by KB/ara-C and KB/ara-C/VCR or of VCR by KB/VCR and KB/ara-C/VCR. KB/VCR and KB/ara-C/VCR cells were cross-resistant to vinblastine, colchicine, vindesine, etoposide, mitomycin C, and Adriamycin. Cells of the two groups (KB/p and KB/ara-C; KB/VCR and KB/ara-C/VCR) differed in sizes and doubling times. In the absence of ara-C, the resistance of KB/ara-C cells to ara-C was stable for at least 1 year, whereas in the absence of VCR resistance to VCR was almost completely lost within 1 month.