Augmentation of 1-beta-D-arabinofuranosylcytosine resistance in human KB epidermoid carcinoma cells upon induction of a second resistance to vincristine.
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 460-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 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.
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D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D003561:Cytarabine / Q000378:metabolism / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D007624:KB Cells / Q000187:drug effects / Q000378:metabolism; D014750:Vincristine / Q000378:metabolism / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D003561:Cytarabine; D014750:Vincristine