Use of camptothecin-resistant mammalian cell lines to evaluate the role oftopoisomerase I in the antiproliferative activity of the indolocarbazole, NB-506, and its topoisomerase I binding site
Y. Urasaki et al., Use of camptothecin-resistant mammalian cell lines to evaluate the role oftopoisomerase I in the antiproliferative activity of the indolocarbazole, NB-506, and its topoisomerase I binding site, CANCER RES, 61(2), 2001, pp. 504-508
NB-506 is a topoisomerase I (top1) inhibitor in clinical trials. In this st
udy, we used a series of camptothecin (CPT)-resistant cell lines with known
top1 alterations, We show that three mutations in different domains of the
top1 enzyme that confer CPT resistance also confer cross-resistance to NB-
506. The CPT-resistant cell lines and corresponding mutations were: human p
rostate carcinoma cells DU-145/RC1 (mutation R364H), Chinese hamster fibrob
lasts DC3F/C10 (mutation G503S), and human leukemia CEM/C2 cells (N722S), T
his result suggests that NB-506 and CPT share a common binding site in the
top1-DNA complex, We next used these three cell lines and their parental ce
lls to study the relationship between top1 poisoning by NB-506 and antiprol
iferative activity, We Pound that the CPT-resistant cells were only 2-10-fo
ld resistant to NB-506, which suggests that NB-506 targets other cellular p
rocesses/pathways besides top1, This conclusion was further supported by th
e limited cross-resistance of top1-deficient murine leukemia P388/CPT45 cel
ls (2-fold). Cross-resistance was also limited for J-109,382, an isomer of
NB-506 that does not intercalate into DNA, indicating that the non-top1-med
iated antiproliferative activity of NB-506 is not attributable to DNA inter
calation,Together, these data indicate that NB-506 and indolocarbazoles are
promising agents to overcome CPT resistance.