XB596, A PROMISING BIS-NAPHTHALIMIDE ANTICANCER AGENT

We have synthesized a promising class of bis-naphthalimide anti-tumor agents. A representative compound in this series, XB596, exhibits pote nt in vitro growth inhibitory activity against several human and murin e 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 ag ainst three doxorubicin-resistant cell lines compared with their paren tal lines. Using a human tumor colony-forming assay, XB596 demonstrate d cytocidal activity against fresh human tumors taken directly from pa tients, with 23 of 25 evaluable tumors responding to a continuous expo sure of 1 mug/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 muM. DNA single-s trand breaks, but not double-strand breaks, were detected in XB596-tre ated L1210 cells. XB596 bound to DNA with guanine-cytosine sequence se lectivity as shown by an indirect ethidium bromide displacement assay. XB596 was showns to interact with DNA by a spectrophotometric titrati on assay, with an estimated binding constant of 4.7 +/- 2.2 +/- 10(6) M-1. XB596 unwound supercoiled DNA as measured by agarose gel electrop horesis. These data are consistent with XB596 being a DNA intercalator . In vivo, XB596 demonstrated good anti-tumor activity against two hum an solid tumors (DLD-2 colon adenocarcinoma and MX-1 mammary carcinoma ) xeonografted in nude mice, but has not demonstrated anti-leukemic ac tivity. In summary, XB596 is a pre-clinical anti-cancer agent which in teracts with DNA and demonstrates good in vivo anti-tumor activity aga inst human solid tumor xenografts.