We have synthesized a promising class of bis-
naphthalimide anti-
tumor agents. A representative compound in this series,
XB596, exhibits potent in vitro growth inhibitory activity against several human and murine leukemic and solid
tumor lines in culture, with IC50 values ranging from 7.2 to 147.5 nM.
XB596 was almost as equally growth inhibitory against three
doxorubicin-resistant cell lines compared with their parental lines. Using a human
tumor colony-forming assay,
XB596 demonstrated cytocidal activity against fresh human
tumors taken directly from patients, with 23 of 25 evaluable
tumors responding to a continuous exposure of 1 microgram/ml of
XB596. When L1210 cells were incubated with
XB596 for 1 h, the incorporation of
uridine and
thymidine into
RNA and
DNA, respectively, was inhibited with IC50 values of 0.14 microM.
DNA single-strand breaks, but not double-strand breaks, were detected in XB596-treated L1210 cells.
XB596 bound to
DNA with
guanine-
cytosine sequence selectivity as shown by an indirect
ethidium bromide displacement assay.
XB596 was shown to interact with
DNA by a spectrophotometric titration assay, with an estimated binding constant of 4.7 +/- 2.2 +/- 10(6) M-1.
XB596 unwound
supercoiled DNA as measured by
agarose gel electrophoresis. These data are consistent with
XB596 being
a DNA intercalator. In vivo,
XB596 demonstrated good anti-
tumor activity against two human solid
tumors (DLD-2
colon adenocarcinoma and MX-1 mammary
carcinoma) xenografted in nude mice, but has not demonstrated anti-leukemic activity. In summary,
XB596 is a pre-clinical anti-
cancer agent which interacts with
DNA and demonstrates good in vivo anti-
tumor activity against human solid
tumor xenografts.