| Abstract |
In this study the in-vitro susceptibility of murine myeloid precursors
(GM-CFU) and murine leukemia cells (WEHI-3B(D+) and L1210 lines) to
ciprofloxacin (CPX), lomefloxacin (LMX), ofloxacin (OFX), pefloxacin (PFX)
and rufloxacin (RFX) was compared. The two leukemia lines were equally
susceptible and significantly more sensitive than GM-CFU. To develop a
model for studying the mechanism of the inhibitory effect, we established
a WEHI-3B(D+) subclone resistant to CPX (WEHI-3B/CPX). The IC50 of CPX for
the resistant variant was 17.3 times higher than that for the parental
line and the resistance was not reversed by verapamil. Further, the
resistance of the WEHI-3B/CPX variant towards either other quinolones
(IC50 ratios from 1.12 to 1.83) or to other topoisomerase II inhibitors
such as VP-16, VM-26 and adriamycin (IC50 ratios ranging from 0.96 to 1.
22) did not increase significantly. The WEHI-3B/CPX variant expresses CPX
resistance for 60 passages (13 months) in the absence of the selecting
agent, suggesting genetic stability. CPX uptake by the variant clone was
reduced by 50%, however, as observed by Western blotting, P-170
glycoprotein was not expressed. The variant clone and the wild type line
were tested for their proliferative capacity, agar clonogenicity and IL-3
production and no significant differences were noted. These observations
confirm that quinolones act on the proliferation of mammalian cells
producing a dose dependent-inhibition and that leukemia cells show a
greater sensitivity to this inhibitory action in comparison with normal
myeloid cells. Further, since the WEHI-3B/CPX cell line is a genetically
stable CPX-resistant variant with a phenotype which is not cross-resistant
to other quinolones, novobiocin, and antineoplastic drugs active on
topoisomerase II, it represents a new, interesting model for studying the
mechanism of drug resistance of mammalian cells.
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