Abstract |
Two human myelomonocytic leukemia cell lines highly resistant to 1-beta-D-
arabinofuranosylcytosine (ara-C) were established. One line, designated KY-Ra,
has been proliferating with 1x10^-4 M ara-C for over one year. The
other one, KY-Rb, has proliferated with 1x10-5 M N^4-behenoyl-1-beta-D-
arabinofuranosylcytosine (BH-AC) after it reached a proliferative capacity
with 1x10^-6 M ara-C. These two ara-C-resistant cell lines have shown
approximately 5,900 fold and 18,000 fold resistance to ara-C over the
parental KY-821 cell line. The deoxycytidine kinase activity of each cell
line was 0.39 (dCMP/min/mug protein) for KY-Ra, 0.26 for KY-Rb, 1.23 for
KY-821. Deoxycytidine deaminase activities were almost identical. In drug
accumulations, ara-C resistant cell lines showed a reduced uptake of ara-C
during a 4 h exposure to 1 nM ara-C. After loading almost the same
intracellular contents of drugs, ara-CTP accumulation decreased in two ara-C
resistant cell lines, and the efflux rate was increased in KY-Ra. These
results indicate that the decreased deoxycytidine kinase activity, which
resulted in a decreased ara-CTP accumulation, is one of major mechanisms
of the resistance, and suggest the possibility that an increase of the
outward flux of ara-C is one mechanism of resistance. These cell lines may
be useful for studying the refractoriness encountered in ara-C
administration.
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